Name: Team FPS

Posts by Team FPS:

    T3 Therapy to Reset Low Body Temperature in Hypothyroidism

    January 23rd, 2017

    Also see:
    Wilson’s Temperature Syndrome
    Basis Guidelines Wilson T3 Protocol
    Wilson’s Temperature Tracking Chart
    Wilson’s low Temperature Syndrome
    Wilson Treatment Guidelines
    Ray Peat, PhD on Thyroid, Temperature, Pulse, and TSH
    Dosing with T3-only (or with low-dose NDT, or the combination of T4/T3)

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    Bodily Resources vs Demands

    August 1st, 2016

    Also see:
    Stress — A Shifting of Resources
    Collection of FPS Charts
    Sugar (Sucrose) Restrains the Stress Response
    Low Blood Sugar Basics
    Ray Peat, PhD on Low Blood Sugar & Stress Reaction
    Bowel Toxins Accelerate Aging
    Exercise Induced Stress
    Carbohydrate Lowers Exercise Induced Stress
    Low Carb Diet – Death to Metabolism
    Can Endurance Sports Really Cause Harm? The Lipopolysaccharides of Endotoxemia and Their Effect on the Heart
    Running on Empty
    Exercise and Endotoxemia
    Ray Peat, PhD on Endotoxin
    Endotoxin: Poisoning from the Inside Out
    Ray Peat, PhD: Quotes Relating to Exercise

    “Life is a condition alternating between excitation, destruction and unbalance, and reorganization, equilibrium and rest.” -Kurt Goldstein

    The bucket pictogram below, inspired the efforts of from James Clear, explains many health concepts. The body resources bucket contains some of the primary factors that ensure good health. These resources are drained by the body’s demands (dotted arrow), which vary from person to person.

    Bodily Resources vs Demands

    Bodily Resources vs Demands

    The global objective is to maximize bodily resources and minimize demands to avoid momentary or permanent changes in bodily function. Tilt the scales in your favor.

    Screen Shot 2016-08-01 at 7.56.30 PM

    The body’s resources are finite, and the rate at which they are depleted is determined by your body’s demands. Maintain body balance by ensuring that your resources always trump your body’s demands by continually depositing resources on a daily basis and reducing demands where possible.

    Young people are free of disease because their bodily resources are so vast that demands are easily met. When young people are compromised, they recover easily because they can quickly tilt the scales back in their favor.

    There are direct parallels between finance and these two buckets. The resources bucket is analogous to a savings account, and the demands bucket represents total expenses. Don’t spend more money than you have to avoid financial turmoil or bankruptcy. Make deposits into your resources bucket on a daily basis and reduce expenses/demands to ensure protection from resource bankruptcy and a compromised body.

    Here are some additional bullet points:

    • The contents of each bucket will vary for each person. Some of the most basic elements are listed that apply to most people.
    • Weight management and health concerns at their base come about due to imbalance between resources and demands. Each person has his/her own adaptation to the imbalance. Consider how robust your resources are at present and have been over your lifespan. Your present state is a reflection of all your years put together.
    • Simple example of this pictogram at work is when one gets a cold or sickness. Someone gets a cold because demands were excessive relative to their (immune) resources. When someone gets a cold, he/she doesn’t go exercise vigorously (which is another demand) because energy levels and appetite are low. Rather, he/she builds lowers demands by taking time off from work/school if possible and sleeping/resting more and eventually eating well to build up his/her resources again to achieve recovery. If a person cannot aggregate the resources necessary to overcome the illness, the illness remains. How often you get sick and how long it takes you to recover when you do get sick is one indicator of how robust your resources bucket is.
    • Restorative sleep and midday naps are an outstanding way to lower demands on your system.
    • A person with sleep difficulties (sleep apnea, mouth breathing while sleeping, insomnia, waking several times during the night, waking feeling unrested, nocturnal urination, teeth grinding) is often the individual with high demands but low available resources. This creates a vicious cycle because of the inability to lower demands significantly via restorative sleep.

    Additional Resources:
    “The Stress of Life” by Hans Selye (book)
    “Stress Without Distress” by Hans Selye (book)
    “Why Zebras Don’t Get Ulcers” by Robert Sapolsky (book)
    “Theory of Cumulative Stress – How to Recover When Stress Builds Up” by James Clear (online)

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    Calcium to Phosphorus Ratio of Vegetables and Fruits

    July 18th, 2016

    Also see:
    Calcium to Phosphorus Ratio, PTH, and Bone Health
    Calcium to Phosphorus Ratio of Milk, Cheeses, Ice Cream by DrJ on RayPeatForum
    Calcium Paradox
    Source of Dietary Calcium: Chicken Egg Shell Powder
    Low CO2 in Hypothyroidism
    Blood Pressure Management with Calcium & Dairy
    Hypertension and Calcium Deficiency
    Excess Dietary Phosphorus Lowers Vitamin D Levels
    Fatty Acid Synthase (FAS), Vitamin D, and Cancer
    Phosphate, activation, and aging
    Parmigiano Reggiano cheese and bone health
    Preparing Powdered Eggshells for Calcium
    Dairy, Calcium, and Weight Management in Adults and Children

    Quotes by Ray Peat, PhD:
    “The ratio of calcium to phosphate is very important; that’s why milk and cheese are so valuable for weight loss, or for preventing weight gain. For people who aren’t very active, low fat milk and cheese are better, because the extra fat calories aren’t needed.”

    “The foods highest in phosphate, relative to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added phosphate. Foods with a higher, safe ratio of calcium to phosphate are leaves, such as kale, turnip greens, and beet greens, and many fruits, milk, and cheese.”

    “Recent publication are showing that excess phosphate can increase inflammation, tissue atrophy, calcification of blood vessels, cancer, dementia, and, in general, the processes of aging.”


    This is a useful chart of fruits and vegetables ordered from highest to lowest calcium to phosphorus ratio (Ca:P). A ratio of 1.3:1 or higher is best to help keep parathyroid hormone down and protect cells from energy slowdowns and soft tissues from hardening/calcifying. The fruits and vegetables with a good ratio complement the consumption of milk and cheese.

    Chart Source

    GUINEA LYNX’ Sortable Veg & Fruit Chart
    Pre-sorted to Ca:P
    10 Calorie Quantities
    Grams Sugar gm Calcium mg Ca:P Phos mg Magn mg Pot mg Sodium mg Vit_A RAE Vit_C mg
    COLLARDS 33 0.15 48.33 14.5:1 3.33 3.00 56.33 6.67 111.00 11.77
    BUTTERBUR,(FUKI) 71 UNKN 73.57 8.6:1 8.57 10.00 467.86 5.00 2.14 22.50
    MUSTARD SPINACH,(TENDERGREEN) 45 UNKN 95.46 7.5:1 12.73 5.00 204.09 9.55 225.00 59.09
    PAPAYAS 26 1.51 6.15 4.8:1 1.28 2.60 65.90 0.77 14.10 15.85
    TURNIP GREENS 31 0.25 59.38 4.5:1 13.13 9.70 92.50 12.50 180.94 18.75
    LAMBSQUARTERS 23 UNKN 71.86 4.3:1 16.74 7.90 105.12 10.00 134.88 18.61
    DILL WEED,FRSH 23 UNKN 48.37 3.2:1 15.35 12.80 171.63 14.19 89.77 19.77
    BASIL,FRESH 43 0.13 76.96 3.2:1 24.35 27.80 128.26 1.74 114.78 7.83
    ARUGULA 40 0.82 64.00 3.1:1 20.80 18.80 147.60 10.80 47.60 6.00
    ORANGES,ALL COMM VAR 21 1.99 8.51 2.9:1 2.98 2.10 38.51 UNKN 2.34 11.32
    BEET GREENS 45 0.23 53.18 2.9:1 18.64 31.80 346.36 102.73 143.64 13.64
    CABBAGE,CHINESE (PAK-CHOI) 77 0.91 80.77 2.8:1 28.46 14.60 193.85 50.00 171.54 34.62
    DANDELION GREENS 22 0.16 41.56 2.8:1 14.67 8.00 88.22 16.89 112.89 7.78
    CABBAGE,CHINESE (PE-TSAI) 63 0.88 48.13 2.7:1 18.13 8.10 148.75 5.63 10.00 16.88
    KALE 20 UNKN 27.00 2.4:1 11.20 6.80 89.40 8.60 153.80 24.00
    MUSTARD GREENS 38 0.62 39.62 2.4:1 16.54 12.30 136.15 9.62 201.92 26.92
    PARSLEY 28 0.24 38.33 2.4:1 16.11 13.90 153.89 15.56 116.94 36.94
    MELONS,CASABA 36 2.03 3.93 2.2:1 1.79 3.90 65.00 3.21 UNKN 7.79
    NEW ZEALAND SPINACH 71 UNKN 41.43 2.1:1 20.00 27.90 92.86 92.86 157.14 21.43
    WATERCRESS 91 0.18 109.09 2.0:1 54.55 19.10 300.00 37.27 145.46 39.09
    SPINACH 43 0.18 43.04 2.0:1 21.30 34.40 242.61 34.35 203.91 12.22
    SQUASH,WNTR,SPAGHETTI 32 UNKN 7.42 1.9:1 3.87 3.90 34.84 5.48 0.97 0.68
    ENDIVE 59 0.15 30.59 1.9:1 16.47 8.80 184.71 12.94 63.53 3.82
    TANGERINES,(MANDARIN ORANGES) 19 1.76 6.98 1.8:1 3.77 2.30 31.32 0.38 6.42 5.04
    CELERY 63 1.14 25.00 1.7:1 15.00 6.90 162.50 50.00 13.75 1.94
    PINEAPPLE,ALL VAR 20 1.97 2.60 1.6:1 1.60 2.40 21.80 0.20 0.60 9.56
    PURSLANE 63 UNKN 40.63 1.5:1 27.50 42.50 308.75 28.13 41.25 13.13
    ANISE SEED 3 UNKN 19.17 1.5:1 13.06 5.10 42.76 0.48 0.48 0.62
    CABBAGE 40 1.28 16.00 1.5:1 10.40 4.80 68.00 7.20 2.00 14.64
    CABBAGE,RED 32 1.24 14.52 1.5:1 9.68 5.20 78.39 8.71 18.07 18.39
    SQUASH,WNTR,BUTTERNUT 22 0.49 10.67 1.5:1 7.33 7.60 78.22 0.89 118.22 4.67
    BROCCOLI RAAB 45 0.17 49.09 1.5:1 33.18 10.00 89.09 15.00 59.55 9.18
    CORIANDER (CILANTRO) LEAVES 43 0.38 29.13 1.4:1 20.87 11.30 226.52 20.00 146.52 11.74
    RADISHES 63 1.16 15.63 1.3:1 12.50 6.30 145.63 24.38 UNKN 9.25
    BLACKBERRIES 23 1.14 6.74 1.3:1 5.12 4.70 37.67 0.23 2.56 4.88
    SQUASH,WNTR,ALL VAR 29 0.65 8.24 1.2:1 6.77 4.10 102.94 1.18 20.00 3.62
    LETTUCE,GRN LEAF 67 0.52 24.00 1.2:1 19.33 8.70 129.33 18.67 246.67 12.00
    LETTUCE,RED LEAF 63 0.30 20.63 1.2:1 17.50 7.50 116.88 15.63 234.38 2.31
    CHERRIES,SOUR,RED 20 1.70 3.20 1.1:1 3.00 1.80 34.60 0.60 12.80 2.00
    CRESS,GARDEN 31 1.38 25.31 1.1:1 23.75 11.90 189.38 4.38 108.13 21.56
    TURNIPS 36 1.36 10.71 1.1:1 9.64 3.90 68.21 23.93 UNKN 7.50
    CARROTS,BABY 29 1.36 9.14 1.1:1 8.00 2.90 67.71 22.29 197.14 0.74
    LETTUCE,BUTTERHEAD (INCL BOSTON&BIBB TYPES) 77 0.72 26.92 1.1:1 25.39 10.00 183.08 3.85 127.69 2.85
    LETTUCE,COS OR ROMAINE 59 0.70 19.41 1.1:1 17.65 8.20 145.29 4.71 256.47 14.12
    CHARD,SWISS 53 0.58 26.84 1.1:1 24.21 42.60 199.47 112.11 161.05 15.79
    KIWIFRUIT,GRN 16 1.47 5.57 1.0:1 5.57 2.80 51.15 0.49 0.66 15.20
    BEANS,SNAP,GREEN 32 1.05 11.94 1.0:1 12.26 8.10 68.07 1.94 11.29 3.94
    SQUASH,WINTER,ACORN 25 UNKN 8.25 0.9:1 9.00 8.00 86.75 0.75 4.50 2.75
    MANGOS 15 2.28 1.54 0.9:1 1.69 1.40 24.00 0.31 5.85 4.26
    LETTUCE,ICEBERG (INCL CRISPHEAD TYPES) 71 1.41 12.86 0.9:1 14.29 5.00 100.71 7.14 17.86 2.00
    CARROTS 24 1.16 8.05 0.9:1 8.54 2.90 78.05 16.83 203.66 1.44
    RASPBERRIES 19 0.85 4.81 0.9:1 5.58 4.20 29.04 0.19 0.39 5.04
    SALSIFY,(VEG OYSTER) 12 UNKN 7.32 0.8:1 9.15 2.80 46.34 2.44 UNKN 0.98
    PEARS 17 1.69 1.55 0.8:1 1.90 1.20 20.52 0.17 0.17 0.72
    RUTABAGAS 28 1.56 13.06 0.8:1 16.11 6.40 93.61 5.56 UNKN 6.94
    PEAS,EDIBLE-PODDED 24 0.95 10.24 0.8:1 12.62 5.70 47.62 0.95 12.86 14.29
    CABBAGE,SAVOY 37 0.84 12.96 0.8:1 15.56 10.40 85.19 10.37 18.52 11.48
    SQUASH,WINTER,HUBBARD 25 UNKN 3.50 0.7:1 5.25 4.80 80.00 1.75 17.00 2.75
    SQUASH,SMMR,CROOKNECK&STRAIGHTNECK 53 1.86 11.05 0.7:1 16.84 10.50 116.84 1.05 4.21 10.16
    STRAWBERRIES 31 1.53 5.00 0.7:1 7.50 4.10 47.81 0.31 0.31 18.38
    CUCUMBER,WITH PEEL 67 1.11 10.67 0.7:1 16.00 8.70 98.00 1.33 3.33 1.87
    BROCCOLI 29 0.50 13.82 0.7:1 19.41 6.20 92.94 9.71 9.12 26.24
    MELONS,CANTALOUPE 29 2.31 2.65 0.6:1 4.41 3.50 78.53 4.71 49.71 10.79
    WATERMELON 33 2.07 2.33 0.6:1 3.67 3.30 37.33 0.33 9.33 2.70
    CHERRIES,SWEET 16 2.04 2.06 0.6:1 3.33 1.80 35.24 UNKN 0.48 1.11
    CRANBERRIES 22 0.88 1.74 0.6:1 2.83 1.30 18.48 0.44 0.65 2.89
    BRUSSELS SPROUTS 23 0.51 9.77 0.6:1 16.05 5.40 90.47 5.81 8.84 19.77
    SWEET POTATO,UNPREP 12 0.49 3.49 0.6:1 5.47 2.90 39.19 6.40 82.44 0.28
    RADISH SEEDS,SPROUTED 23 UNKN 11.86 0.5:1 26.28 10.20 20.00 1.40 4.65 6.72
    SQUASH,SUMMER,SCALLOP 56 UNKN 10.56 0.5:1 20.00 12.80 101.11 0.56 3.33 10.00
    PEPPERS,SWEET,YELLOW 37 UNKN 4.07 0.5:1 8.89 4.40 78.52 0.74 3.70 67.96
    MELONS,HONEYDEW 28 2.26 1.67 0.5:1 3.06 2.80 63.33 5.00 0.83 5.00
    GRAPES,RED OR GRN (EURO TYPE,SUCH AS THOMPSON SEEDLESS) 14 2.24 1.45 0.5:1 2.90 1.00 27.68 0.29 0.44 1.57
    APPLES,WITH SKIN 19 2.00 1.15 0.5:1 2.12 1.00 20.58 0.19 0.58 0.89
    RAISINS,SEEDLESS 3 1.98 1.67 0.5:1 3.38 1.10 25.05 0.37 UNKN 0.08
    RAISINS,GOLDEN SEEDLESS 3 1.96 1.76 0.5:1 3.81 1.20 24.70 0.40 UNKN 0.11
    BLUEBERRIES 18 1.75 1.05 0.5:1 2.11 1.10 13.51 0.18 0.53 1.70
    PEPPERS,SWT,GRN 50 1.20 5.00 0.5:1 10.00 5.00 87.50 1.50 9.00 40.20
    KOHLRABI 37 0.96 8.89 0.5:1 17.04 7.00 129.63 7.41 0.74 22.96
    ASPARAGUS 50 0.94 12.00 0.5:1 26.00 7.00 101.00 1.00 19.00 2.80
    CAULIFLOWER 40 0.76 8.80 0.5:1 17.60 6.00 119.60 12.00 UNKN 19.28
    PARSNIPS 13 0.64 4.80 0.5:1 9.47 3.90 50.00 1.33 UNKN 2.27
    PUMPKIN 38 0.52 8.08 0.5:1 16.92 4.60 130.77 0.39 141.92 3.46
    RADICCHIO 43 0.26 8.26 0.5:1 17.39 5.70 131.30 9.57 0.44 3.48
    ALFALFA SEEDS,SPROUTED 43 0.08 13.91 0.5:1 30.44 11.70 34.35 2.61 3.48 3.57
    SWEET POTATO LEAVES 29 UNKN 10.57 0.4:1 26.86 17.40 148.00 2.57 14.57 3.14
    PLUMS 22 2.16 1.30 0.4:1 3.48 1.50 34.13 UNKN 3.70 2.07
    PEARS,ASIAN 24 1.68 0.95 0.4:1 2.62 1.90 28.81 UNKN UNKN 0.91
    BEETS 23 1.57 3.72 0.4:1 9.30 5.40 75.58 18.14 0.47 1.14
    SQUASH,SMMR,ZUCCHINI,INCL SKN 59 1.47 9.41 0.4:1 22.35 10.60 153.53 4.71 5.88 10.53
    TOMATOES,RED,RIPE,YEAR RND AVERAGE 56 1.46 5.56 0.4:1 13.33 6.10 131.67 2.78 23.33 7.06
    SQUASH,SMMR,ALL VAR 63 1.38 9.38 0.4:1 23.75 10.60 163.75 1.25 6.25 10.63
    BEANS,FAVA,IN POD 11 UNKN 4.21 0.3:1 14.66 3.80 37.73 2.84 1.93 0.42
    PEACHES 26 2.15 1.54 0.3:1 5.13 2.30 48.72 UNKN 4.10 1.69
    PEPPERS,SWT,RED 32 1.36 2.26 0.3:1 8.39 3.90 68.07 1.29 50.65 41.19
    YAM 8 0.04 1.44 0.3:1 4.66 1.80 69.15 0.76 0.59 1.45
    SQUASH,ZUCCHINI,BABY 48 UNKN 10.00 0.2:1 44.29 15.70 218.57 1.43 11.91 16.24
    PEAS,MATURE SEEDS,SPROUTED 8 UNKN 2.90 0.2:1 13.31 4.50 30.73 1.61 UNKN 0.84
    NECTARINES 23 1.79 1.36 0.2:1 5.91 2.10 45.68 UNKN 3.86 1.23
    BANANAS 11 1.37 0.56 0.2:1 2.47 3.00 40.23 0.11 0.34 0.98
    PEAS,GREEN 12 0.70 3.09 0.2:1 13.33 4.10 30.12 0.62 4.69 4.94
    LENTILS,SPROUTED 9 UNKN 2.36 0.1:1 16.32 3.50 30.38 1.04 0.19 1.56
    OATS 3 UNKN 1.39 0.1:1 13.45 4.60 11.03 0.05 UNKN UNKN
    WHEAT GERM,CRUDE 3 UNKN 1.08 0.0:1 23.39 6.60 24.78 0.33 UNKN UNKN
    CORN,SWT,YEL 12 0.73 0.23 0.0:1 10.35 4.30 31.40 1.74 1.05 0.79
    CEREALS RTE,WHEAT GERM,TSTD,PLN 3 0.20 1.18 0.0:1 30.00 8.40 24.79 0.11 0.13 0.16

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    Scott Sonnon Intuflow Joint Mobility

    June 22nd, 2016



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    Low Estrogen Content in Milk

    June 1st, 2016

    Also see:
    Toxic Plant Estrogens
    Calcium to Phosphorus Ratio, PTH, and Bone Health
    Calcium Paradox
    Source of Dietary Calcium: Chicken Egg Shell Powder
    Low CO2 in Hypothyroidism
    Blood Pressure Management with Calcium & Dairy
    Hypertension and Calcium Deficiency
    Excess Dietary Phosphorus Lowers Vitamin D Levels
    Fatty Acid Synthase (FAS), Vitamin D, and Cancer
    Phosphate, activation, and aging
    Parmigiano Reggiano cheese and bone health
    Preparing Powdered Eggshells for Calcium
    Dairy, Calcium, and Weight Management in Adults and Children

    Key thoughts:
    1. Low estrogen concentrations in milk.
    2. More dietary fat equates to more estrogen content.
    3. Goat milk has less estrogen than cow’s milk although both are low.
    4. A study reporting high estrogen content in milk should also measure progesterone levels.


    J Dairy Sci. 2010 Jun;93(6):2533-40. doi: 10.3168/jds.2009-2947.
    Estrone and 17beta-estradiol concentrations in pasteurized-homogenized milk and commercial dairy products.
    Pape-Zambito DA1, Roberts RF, Kensinger RS.
    Some individuals fear that estrogens in dairy products may stimulate growth of estrogen-sensitive cancers in humans. The presence of estrone (E(1)) and 17beta-estradiol (E(2)) in raw whole cow’s milk has been demonstrated. The objectives of this study were to determine if pasteurization-homogenization affects E(2) concentration in milk and to quantify E(1) and E(2) concentrations in commercially available dairy products. The effects of pasteurization-homogenization were tested by collecting fresh raw milk, followed by pasteurization and homogenization at 1 of 2 homogenization pressures. All treated milks were tested for milk fat globule size, percentages of milk fat and solids, and E(2) concentrations. Estrone and E(2) were quantified from organic or conventional skim, 1%, 2%, and whole milks, as well as half-and-half, cream, and butter samples. Estrone and E(2) were quantified by RIA after organic solvent extractions and chromatography. Pasteurization-homogenization reduced fat globule size, but did not significantly affect E(2), milk fat, or milk solids concentrations. Estrone concentrations averaged 2.9, 4.2, 5.7, 7.9, 20.4, 54.1 pg/mL, and 118.9 pg/g in skim, 1%, 2%, and whole milks, half-and-half, cream, and butter samples, respectively. 17Beta-estradiol concentrations averaged 0.4, 0.6, 0.9, 1.1, 1.9, 6.0 pg/mL, and 15.8 pg/g in skim, 1%, 2%, whole milks, half-and-half, cream, and butter samples, respectively. The amount of fat in milk significantly affected E(1) and E(2) concentrations in milk. Organic and conventional dairy products did not have substantially different concentrations of E(1) and E(2). Compared with information cited in the literature, concentrations of E(1) and E(2) in bovine milk are small relative to endogenous production rates of E(1) and E(2) in humans.

    J Dairy Sci. 2007 Jul;90(7):3308-13.
    Concentrations of 17beta-estradiol in Holstein whole milk.
    Pape-Zambito DA1, Magliaro AL, Kensinger RS.
    Some individuals have expressed concern about estrogens in food because of their potential to promote growth of estrogen-sensitive human cancer cells. Researchers have reported concentrations of estrogen in milk but few whole milk samples have been analyzed. Because estrogen associates with the fat phase of milk, the analysis of whole milk is an important consideration. The objectives of this study, therefore, were to quantify 17beta-estradiol (E2) in whole milk from dairy cows and to determine whether E2 concentrations in milk from cows in the second half of pregnancy were greater than that in milk from cows in the first half of pregnancy or in nonpregnant cows. Milk samples and weights were collected during a single morning milking from 206 Holstein cows. Triplicate samples were collected and 2 samples were analyzed for fat, protein, lactose, and somatic cell counts (SCC); 1 sample was homogenized and analyzed for E2. The homogenized whole milk (3 mL) was extracted twice with ethyl acetate and once with methanol. The extract was reconstituted in benzene:methanol (9:1, vol/vol) and run over a Sephadex LH-20 column to separate E2 from cholesterol and estrone before quantification using radioimmunoassay. Cows were classified as not pregnant (NP, n = 138), early pregnant (EP, 1 to 140 d pregnant, n = 47), or midpregnant (MP, 141 to 210 d pregnant, n = 21) at the time of milk sampling based on herd health records. Mean E2 concentration in whole milk was 1.4 +/- 0.2 pg/mL and ranged from nondetectable to 22.9 pg/mL. Milk E2 concentrations averaged 1.3, 0.9, and 3.0 pg/mL for NP, EP, and MP cows, respectively. Milk E2 concentrations for MP cows were greater and differed from those of NP and EP cows. Milk composition was normal for a Holstein herd in that log SCC values and percentages of fat, protein, and lactose averaged 4.9, 3.5, 3.1, and 4.8, respectively. Estradiol concentration was significantly correlated (r = 0.20) with percentage fat in milk. Mean milk yield was 18.9 +/- 0.6 kg for the morning milking. The mean E2 mass accumulated in the morning milk was 23.2 +/- 3.4 ng/cow. Likewise, using the overall mean concentration for E2 in milk, the mean E2 mass in 237 mL (8 fluid ounces) of raw whole milk was 330 pg. The quantity of E2 in whole milk, therefore, is low and is unlikely to pose a health risk for humans.

    J Dairy Sci. 1979 Sep;62(9):1458-63.
    Measurement of estrogens in cow’s milk, human milk, and dairy products.
    Wolford ST, Argoudelis CJ.
    Free natural estrogens in raw and commercial whole milk were quantitated by radioimmunoassay. The ranges of concentration of estrone, estradiol 17-beta, and estriol were 34 to 55, 4 to 14, and 9 to 31 pg/ml. Proportions of active estrogens (estrone and estradiol) in the fat phases of milk by radioactive tracer on separated milk were 80% and 65%. These findings were supported by radioimmunoassay of skim milk and butter. Equilibrium dialysis of skim milk with hydrogen 3 labeled estrogens showed that 84 to 85% of estrone and estradiol and 61 to 66% of estriol were protein bound. Whey proteins demonstrated a greater binding capacity than casein. This result was confirmed by radioimmunoassay of dry curd cottage cheese and whey. The concentrations in curd were 35, 11, and 6 pg/g. In whey they were 4, 2, and 3 pg/ml. The quantity of active estrogens in dairy products is too low to demonstrate biological activity. Butter was highest with concentrations of 539, 82, and 87 pg/g. Human colostrum demonstrated a maximum concentration of 4 to 5 ng/ml for estrone and estriol and about .5 ng/ml for estradiol. By the 5th day postpartum, they decreased to become similar to cow’s milk.

    J Dairy Sci. 2012 Apr;95(4):1699-708. doi: 10.3168/jds.2011-5072.
    Comparison of estrone and 17β-estradiol levels in commercial goat and cow milk.
    Farlow DW1, Xu X, Veenstra TD.
    Increased levels of estrogen metabolites are believed to be associated with cancers of the reproductive system. One potential dietary source of these metabolites that is commonly consumed worldwide is milk. In North America, dairy cows are the most common source of milk; however, goats are the primary source of milk worldwide. In this study, the absolute concentrations of unconjugated and total (unconjugated plus conjugated) estrone (E(1)) and 17β-estradiol (E(2)) were compared in a variety of commercial cow milks (regular and organic) and goat milk. A lower combined concentration of E(1) and E(2) was found in goat milk than in any of the cow milk products tested. The differences in E(1) and E(2) levels between regular and organic cow milks were not as significant as the differences between goat milk and any of the cow milk products. Goat milk represents a better dietary choice for individuals concerned with limiting their estrogen intake.

    Iran J Public Health. 2015 Jun; 44(6): 742–758
    Hormones in Dairy Foods and Their Impact on Public Health – A Narrative Review Article

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    NuSI Hall Study: No Ketogenic Advantage

    May 29th, 2016

    Also See:
    Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets.
    Blood ketones are directly related to fatigue and perceived effort during exercise in overweight adults adhering to low-carbohydrate diets for weight loss: a pilot study.
    PUFA, Ketones, and Sugar Restriction Promote Tumor Growth
    Tumor Bearing Organisms – Lipolysis and Ketogenesis as Signs of Chronic Stress
    Free Fatty Acids Suppress Cellular Respiration
    The Randle Cycle
    Ray Peat, PhD on Low Blood Sugar & Stress Reaction

    Comments Off on NuSI Hall Study: No Ketogenic Advantage

    Polyunsaturating America: Mazola’s Marketing

    February 21st, 2016

    Also see:
    PUFA Promote Cancer
    Unsaturated Fats and Heart Damage
    Gelatin Ads
    Sugar Ads
    Errors in Nutrition: Essential Fatty Acids
    Toxicity of Stored PUFA
    Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
    PUFA Accumulation & Aging
    Maternal PUFA Intake Increases Breast Cancer Risk in Female Offspring
    Israeli Paradox: High Omega -6 Diet Promotes Disease
    Benefits of Aspirin
    Arachidonic Acid’s Role in Stress and Shock
    Charts: Mean SFA, MUFA, & PUFA Content of Various Dietary Fats
    Unsaturated fatty acids: Nutritionally essential, or toxic? by Ray Peat, PhD
    “Curing” a High Metabolic Rate with Unsaturated Fats
    Fat Deficient Animals – Activity of Cytochrome Oxidase
    Anti-Inflammatory Omega -9 Mead Acid (Eicosapentaenoic acid)
    Protective “Essential Fatty Acid Deficiency”
    Cholesterol and Thyroid Connection
    Thyroid Status and Cardiovascular Disease

    A few factors collide starting in the 1970s to further expedite a departure from traditional animal fats towards polyunsaturated plant oils:

    • US government, under Nixon, subsidizes corn (corn oil/Mazola). Government later subsidizes soy and wheat.
    • Cheaper vegetable and seed (liquid) oils progressively replace animal fats, capitalizing on the ridiculous anti-cholesterol campaign and faulty lipid hypothesis.
    • Nutritional information from the government supports American industry, not health.

    Mazola’s marketing campaign in the 1970s put polyunsaturated fats front and center in the American vernacular and placed saturated fats firmly as the bad guy. The marketing encouraged women to “polyunsaturate” their loved ones while avoiding saturates; in retrospect, this is the exact opposite of what is desired.

    Over 40 years later, the US is still suffering from the ubiquitous use of vegetable oils. While milk, sugar, fructose, salt, and saturated fat take a beating from American society as nutritional toxins, polyunsaturated fats in their various forms continue to get a free pass. Evidence from Ray Peat, PhD and the FPS blog will hopefully help people come to their senses.










    Vitamin E Needs Increases with PUFA Consumption and Greater Unsaturation

    February 20th, 2016

    Also See:
    Your MUFA + PUFA Intakes Determine Your True Vitamin E Requirements – N-3s are the Worst Offenders + Even MUFAs Need Buffering | Tool to Calculate Your Individual NeedsVitamin E and Autoimmune Disease
    Autoimmune Disease and Estrogen Connection
    Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
    Toxicity of Stored PUFA
    Israeli Paradox: High Omega -6 Diet Promotes Disease
    PUFA Accumulation & Aging
    Protective “Essential Fatty Acid Deficiency”
    PUFA Promote Stress Response; Saturated Fats Suppress Stress Response
    PUFA, Fish Oil, and Alzheimers

    Int J Vitam Nutr Res. 2000 Mar;70(2):31-42.
    Relationship between vitamin E requirement and polyunsaturated fatty acid intake in man: a review.
    Valk EE1, Hornstra G.
    Vitamin E is the general term for all tocopherols and tocotrienols, of which alpha-tocopherol is the natural and biologically most active form. Although gamma-tocopherol makes a significant contribution to the vitamin E CONTENT in foods, it is less effective in animal and human tissues, where alpha-tocopherol is the most effective chain-breaking lipid-soluble antioxidant. The antioxidant function of vitamin E is critical for the prevention of oxidation of tissue PUFA. Animal experiments have shown that increasing the degree of dietary fatty acid unsaturation increases the peroxidizability of the lipids and reduces the time required to develop symptoms of vitamin E deficiency. From these experiments, relative amounts of vitamin E required to protect the various fatty acids from being peroxidized, could be estimated. Since systematic studies on the vitamin E requirement in relation to PUFA consumption have not been performed in man, recommendations for vitamin E intake are based on animal experiments and human food intake data. An intake of 0.6 mg alpha-tocopherol equivalents per gram linoleic acid is generally seen as adequate for human adults. The minimum vitamin E requirement at consumption of fatty acids with a higher degree of unsaturation can be calculated by a formula, which takes into account the peroxidizability of unsaturated fatty acids and is based on the results of animal experiments. There are, however, no clear data on the vitamin E requirement of humans consuming the more unsaturated fatty acids as for instance EPA (20:5, n-3) and DHA (22:6, n-3). Studies investigating the effects of EPA and DHA supplementation have shown an increase in lipid peroxidation, although amounts of vitamin E were present that are considered adequate in relation to the calculated oxidative potential of these fatty acids. Furthermore, a calculation of the vitamin E requirement, using recent nutritional intake data, shows that a reduction in total fat intake with a concomitant increase in PUFA consumption, including EPA and DHA, will result in an increased amount of vitamin E required. In addition, the methods used in previous studies investigating vitamin E requirement and PUFA consumption (for instance erythrocyte hemolysis), and the techniques used to assess lipid peroxidation (e.g. MDA analysis), may be unsuitable to establish a quantitative relation between vitamin E intake and consumption of highly unsaturated fatty acids. Therefore, further studies are required to establish the vitamin E requirement when the intake of longer-chain, more-unsaturated fatty acids is increased. For this purpose it is necessary to use functional techniques based on the measurement of lipid peroxidation in vivo. Until these data are available, the widely used ratio of at least 0.6 mg alpha-TE/g PUFA is suggested. Higher levels may be necessary, however, for fats that are rich in fatty acids containing more than two double bonds.

    Br J Nutr. 2015 Oct 28;114(8):1113-22. doi: 10.1017/S000711451500272X. Epub 2015 Aug 21.
    Vitamin E function and requirements in relation to PUFA.
    Raederstorff D1, Wyss A1, Calder PC2, Weber P1, Eggersdorfer M1.
    Vitamin E (α-tocopherol) is recognised as a key essential lipophilic antioxidant in humans protecting lipoproteins, PUFA, cellular and intra-cellular membranes from damage. The aim of this review was to evaluate the relevant published data about vitamin E requirements in relation to dietary PUFA intake. Evidence in animals and humans indicates a minimal basal requirement of 4-5 mg/d of RRR-α-tocopherol when the diet is very low in PUFA. The vitamin E requirement will increase with an increase in PUFA consumption and with the degree of unsaturation of the PUFA in the diet. The vitamin E requirement related to dietary linoleic acid, which is globally the major dietary PUFA in humans, was calculated to be 0·4-0·6 mg of RRR-α-tocopherol/g of linoleic acid. Animal studies show that for fatty acids with a higher degree of unsaturation, the vitamin E requirement increases almost linearly with the degree of unsaturation of the PUFA in the relative ratios of 0·3, 2, 3, 4, 5 and 6 for mono-, di-, tri-, tetra-, penta- and hexaenoic fatty acids, respectively. Assuming a typical intake of dietary PUFA, a vitamin E requirement ranging from 12 to 20 mg of RRR-α-tocopherol/d can be calculated. A number of guidelines recommend to increase PUFA intake as they have well-established health benefits. It will be prudent to assure an adequate vitamin E intake to match the increased PUFA intake, especially as vitamin E intake is already below recommendations in many populations worldwide.

    Z Ernahrungswiss. 1991 Sep;30(3):174-80.
    On the problematic nature of vitamin E requirements: net vitamin E.
    Bässler KH1.
    The requirement for vitamin E is closely related to the dietary intake of polyunsaturated fatty acids (PUFA). By the protective mechanism to prevent PUFA from being peroxidized, vitamin E is metabolically consumed. In addition, PUFA impair the intestinal absorption of vitamin E. Therefore PUFA generate an additional vitamin E requirement on the order of 0.6, 0.9, 1.2, 1.5, and 1.8 mg vitamin E (RRR-alpha-tocopherol-equivalents), respectively, for 1 g of dienoic, trienoic, tetraenoic, pentaenoic, and hexaenoic acid. For this reason, the gross vitamin E content of food containing PUFA does not allow an evaluation of this food as a source of vitamin E. A suitable measure is the net vitamin E content, i.e., gross vitamin E minus the amount needed for PUFA protection. Therefore, some food-stuffs generally considered as vitamin-E sources, as concluded from their gross vitamin E content, cause in reality a vitamin E deficiency if not sufficiently compensated by other vitamin E supplying food constituents. Examples of the net vitamin E content of some fats and oils, fish and nuts are shown. Consequences for food composition data and food labeling and the problem of meeting the vitamin-E requirements are discussed.

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    VIDEO: Are Happy Gut Bacteria Key to Weight Loss?

    January 17th, 2016

    Also See:
    Endotoxin: Poisoning from the Inside Out
    Ray Peat, PhD on Endotoxin
    Thumbs Up Fructose
    Protective Effects of Citrus Flavanoid Naringenin
    Bowel Toxins Accelerate Aging
    Ray Peat, PhD on the Benefits of the Raw Carrot
    Protection from Endotoxin
    Endotoxin-lipoprotein Hypothesis
    Protective Bamboo Shoots
    The effect of raw carrot on serum lipids and colon function


    A few years before Super Size Me hit theaters in 2004, Dr. Paresh Dandona, a diabetes specialist in Buffalo, New York, set out to measure the body’s response to McDonald’s—specifically breakfast. Over several mornings, he fed nine normal-weight volunteers an egg sandwich with cheese and ham, a sausage muffin sandwich, and two hash brown patties.

    Dandona is a professor at the State University of New York-Buffalo who also heads the Diabetes-Endocrinology Center of Western New York, and what he observed has informed his research ever since. Levels of a C-reactive protein, an indicator of systemic inflammation, shot up “within literally minutes.” “I was shocked,” he recalls, that “a simple McDonald’s meal that seems harmless enough”—the sort of high-fat, high-carbohydrate meal that 1 in 4 Americans eats regularly—would have such a dramatic effect. And it lasted for hours.

    Inflammation comes in many forms. The swelling of a sprained ankle indicates repairing torn muscle and tendon. The redness and pain around an infected cut signifies the body’s repulsion of microbes. The fever, aches, and pains that accompany the flu represent a body-wide seek-and-destroy mission directed against an invading virus. They’re all essential to survival, the body’s response to a perceived threat or injury. But inflammation can also cause collateral damage, especially when the response is overwhelming—like in septic shock—or when it goes on too long.

    Chronic, low-grade inflammation has long been recognized as a feature of metabolic syndrome, a cluster of dysfunctions that tends to precede full-blown diabetes and that also increases the risk of heart disease, stroke, certain cancers, and even dementia—the top killers of the developed world. The syndrome includes a combination of elevated blood sugar and high blood pressure, low “good” cholesterol, and an abdominal cavity filled with fat, often indicated by a “beer belly.” But recently, doctors have begun to question whether chronic inflammation is more than just a symptom of metabolic syndrome: Could it, in fact, be a major cause?

    For Dandona, who’s given to waxing grandiloquent about the joys of a beer on the porch in his native Delhi, or the superb ice wines from the Buffalo region, the results presented a quandary. Food was a great pleasure in life. Why would Nature be so cruel, he wondered, and punish us just for eating?

    Over the next decade he tested the effects of various foods on the immune system. A fast-food breakfast inflamed, he found, but a high-fiber breakfast with lots of fruit did not. A breakthrough came in 2007 when he discovered that while sugar water, a stand-in for soda, caused inflammation, orange juice—even though it contains plenty of sugar—didn’t.

    The Florida Department of Citrus, a state agency, was so excited it underwrote a subsequent study, and had fresh-squeezed orange juice flown in for it. This time, along with their two-sandwich, two-hash-brown, 910-calorie breakfast, one-third of his volunteers—10 in total—quaffed a glass of fresh OJ. The non-juice drinkers, half of whom drank sugar water, and the other half plain water, had the expected response—inflammation and elevated blood sugar. But the OJ drinkers had neither elevated blood sugar nor inflammation. The juice seemed to shield their metabolism. “It just switched off the whole damn thing,” Dandona says. Other scientists have since confirmed that OJ has a strong anti-inflammatory effect.

    Orange juice is rich in antioxidants like vitamin C, beneficial flavonoids, and small amounts of fiber, all of which may be directly anti-inflammatory. But what caught Dandona’s attention was another substance. Those subjects who ate just the McDonald’s breakfast had increased blood levels of a molecule called endotoxin. This molecule comes from the outer walls of certain bacteria. If endotoxin levels rise, our immune system perceives a threat and responds with inflammation.

    If theories about the interplay of food and intestinal microbes pan out, it could help cure obesity and revolutionize the $66 billion weight loss industry.

    Where had the endotoxin come from? One possibility was the food itself. But there was another possibility. We all carry a few pounds’ worth of microbes in our gut, a complex ecosystem collectively called the microbiota. The endotoxin, Dandona suspected, originated in this native colony of microbes. Somehow, a greasy meal full of refined carbohydrates ushered it from the gut, where it was always present but didn’t necessarily cause harm, into the bloodstream, where it did. But orange juice stopped that translocation cold.

    Dandona’s ongoing experiments—and others like it—could upend much of we thought we knew about the causes of obesity, or just that extra pesky 10 pounds of flab. If what some scientists now suspect about the interplay of food and intestinal microbes pans out, it could revolutionize the $66 billion weight loss industry—and help control the soaring $2.7 trillion we spend on health care yearly. “What matters is not how much you eat,” Dandona says, “but what you eat.”
    EVER SINCE THE DUTCH DRAPER Antonie van Leeuwenhoek first scrutinized his own plaque with a homemade microscope more than three centuries ago and discovered “little living animalcules, very prettily a-moving,” we’ve known that we’re covered in microbes. But as new and cheaper methods for studying these microbes have become available recently, their importance to our health has grown increasingly evident. Scientists now suspect that our microbial communities contribute to a number of diseases, from allergic disorders like asthma and hay fever, to inflammatory conditions like Crohn’s disease, to cancer, heart disease, and obesity.

    We are, numerically speaking, 10 percent human, and 90 percent microbe.

    As newborns, we encounter our first microbes as we pass through the birth canal. Until that moment, we are 100 percent human. Thereafter, we are, numerically speaking, 10 percent human, and 90 percent microbe. Our microbiome contains at least 150 times more genes, collectively, than our human genome. Think of it as a hulking instruction manual compared to a single page to-do list.

    As we mature, we pick up more microbes from breast milk, food, water, animals, soil, and other people. Sometime in childhood, the bustling community of between 500 and 1,000 species stabilizes. Some species are native only to humans, and may have been passed down within the family like heirlooms. Others are generalists—maybe they’ve hopped aboard from pets, livestock, and other animal sources.

    Enterobacter cloacae

    A cluster of Enterobacter cloacae bacteria Eye of Science / Science Source

    Most of our microbes inhabit the colon, the final loop of intestine, where they help us break down fibers, harvest calories, and protect us from micro-marauders. But they also do much, much more. Animals raised without microbes essentially lack a functioning immune system. Entire repertoires of white blood cells remain dormant; their intestines don’t develop the proper creases and crypts; their hearts are shrunken; genes in the brain that should be in the “off” position remain stuck “on.” Without their microbes, animals aren’t really “normal.”

    What do we do for our microbes in return? Some scientists argue that mammals are really just mobile digestion chambers for bacteria. After all, your stool is roughly half living bacteria by weight. Every day, food goes in one end and microbes come out the other. The human gut is roughly 26 feet in length. Hammered flat, it would have a surface area of a tennis court. Seventy percent of our immune activity occurs there. The gut has its own nervous system; it contains as many neurons as the spinal cord. About 95 percent of the body’s serotonin, a neurotransmitter usually discussed in the context of depression, is produced in the gut.

    Children raised in microbially rich environments—with pets, on farms, or attending day care—are at lower risk of allergic diseases.

    So the gut isn’t just where we absorb nutrients. It’s also an immune hub and a second brain. And it’s crawling with microbes. They don’t often cross the walls of the intestines into the blood stream, but they nevertheless change how the immune, endocrine, and nervous systems all work on the other side of the intestine wall.

    Science isn’t always consistent about what, exactly, goes wrong with our microbes in disease situations. But a recurrent theme is that loss of diversity correlates with the emergence of illness. Children in the developing world have many more types of microbes than kids in Europe or North America, and yet generally develop allergies and asthma at lower rates than those in industrialized nations. In the developed world, children raised in microbially rich environments—with pets, on farms, or attending day care—have a lower risk of allergic disease than kids raised in more sterile environments.

    metabolism flowchart

    Those who study human microbial communities fret that they are undergoing an extinction crisis similar to the one afflicting the biosphere at large—and that modern medicine may be partly to blame. Some studies find that babies born by C-section, deprived of their mother’s vaginal microbes at birth, have a higher risk of celiac disease, Type 1 diabetes, and obesity. Early-life use of antibiotics—which tear through our microbial ecosystems like a forest fire—has also been linked to allergic disease, inflammatory bowel disease, and obesity.

    Which brings us to the question more and more scientists are asking: If our microbiota plays a role in keeping us healthy, then how about attacking disease by treating the microbiota? After all, our community of microbes is quite plastic. New members can arrive and take up residence. Old members can get flushed out. Member ratios can shift. The human genome, meanwhile, is comparatively stiff and unresponsive. So the microbiota represents a huge potential leverage point in our quest to treat, and prevent, chronic disease. In particular, the “forgotten organ,” as some call the microbiota, may hold the key to addressing our single greatest health threat: obesity.
    PARESH DANDONA LEFT INDIA in 1966 for a Rhodes Scholarship at Oxford University. He became “the first colored guy,” he says, to head his unit at the University of London hospital. His bearing—heels together, back stiff, and an orator’s care with words delivered in a deep, sonorous voice—recalls a bygone era. He moved to Buffalo in 1991.

    During those decades, the number of Americans considered obese nearly tripled. One-third of Americans are now considered overweight, and another third obese. Worldwide, one-fourth of humanity is too heavy, according to the World Health Organization. In 2011, the United Nations announced that for the first time ever, chronic diseases, most of which are linked to obesity, killed more people than infectious diseases. In the United States, obesity accounts for 20 percent of health care costs, according to Cornell University economists.

    And the problems aren’t limited to the obese themselves: Children born to obese mothers have hardened arteries at birth, a risk factor for cardiovascular disease. They have a greater risk of asthma. Some studies suggest they’re more likely to suffer from attention deficit disorders and autism.

    Why are we increasingly prone to obesity? The long-dominant explanation is simply that too little exercise and too many calories equals too much stored fat. The solution: more exercise and a lot more willpower. But there’s a problem with this theory: In the developed world, most of us consume more calories than we really need, but we don’t gain weight proportionally.

    A pound of body fat contains roughly 3,500 calories. If you run a daily surplus of just 500 calories—the amount in a bagel with a generous serving of cream cheese—you should, judging by the strict calorie-in-must-equal-calorie-out model, gain a pound of fat per week. Most of us do run a surplus in that range, or even higher, but we either gain weight much more slowly, or don’t gain weight at all.

    Some corpulent people, meanwhile, have metabolisms that work fine. Their insulin and blood sugar levels are within normal range. Their livers are healthy, not marbled with fat. And some thin people have metabolic syndrome, often signaled by a beer gut. They suffer from fatty liver, insulin resistance, elevated blood sugar, high blood pressure, and low-grade, systemic inflammation. From a public health perspective, these symptoms are where the real problem lies—not necessarily how well we fit into our jeans.

    Inflammation might not be a symptom of metabolic syndrome: It could be a cause.

    Here’s the traditional understanding of metabolic syndrome: You ate too much refined food sopped in grease. Calories flooded your body. Usually, a hormone called insulin would help your cells absorb these calories for use. But the sheer overabundance of energy in this case overwhelms your cells. They stop responding to insulin. To compensate, your pancreas begins cranking out more insulin. When the pancreas finally collapses from exhaustion, you have diabetes. In addition, you develop resistance to another hormone called leptin, which signals satiety, or fullness. So you tend to overeat. Meanwhile, fat cells, which have become bloated and stressed as they try to store the excess calories, begin emitting a danger signal—low-grade inflammation.

    But new research suggest another scenario: Inflammation might not be a symptom, it could be a cause. According to this theory, it is the immune activation caused by lousy food that prompts insulin and leptin resistance. Sugar builds up in your blood. Insulin increases. Your liver and pancreas strain to keep up. All because the loudly blaring danger signal—the inflammation—hampers your cells’ ability to respond to hormonal signals. Maybe the most dramatic evidence in support of this idea comes from experiments where scientists quash inflammation in animals. If you simply increase the number of white blood cells that alleviate inflammation—called regulatory T-cells—in obese mice with metabolic syndrome, the whole syndrome fades away. Deal with the inflammation, it seems, and you halt the dysfunction.

    Now, on the face of it, it seems odd that a little inflammation should have such a great impact on energy regulation. But consider: This is about apportioning a limited resource exactly where it’s needed, when it’s needed. When not under threat, the body uses energy for housekeeping and maintenance—and, if you’re lucky, procreation, an optimistic, future-oriented activity. But when a threat arrives—a measles virus, say—you reprioritize. All that hormone-regulated activity declines to a bare minimum. Your body institutes a version of World War II rationing: troops (white blood cells) and resources (calories) are redirected toward the threat. Nonessential tasks, including the production of testosterone, shut down. Forget tomorrow. The priority is to preserve the self today.

    This, some think, is the evolutionary reason for insulin resistance. Cells in the body stop absorbing sugar because the fuel is required—requisitioned, really—by armies of white blood cells. The problems arise when that emergency response, crucial to repelling pillagers in the short term, drags on indefinitely. Imagine it this way. Your dinner is cooking on the stove. You’re paying bills. You smell smoke. You jump up, leaving those tasks half-done, and search for the fire before it burns down your house. Normally, once you put the fire out, you’d return to your tasks and then eat dinner.

    Junk food may not kill us directly, but rather by prompting the collapse of an ancient and mutually beneficial symbiosis.

    But now imagine that you never find the fire, and you never stop smelling the smoke. You remain in a perpetual state of alarm. Your bills never get paid. You never eat your dinner. Your house smolders. Your life falls into disarray.

    That’s metabolic syndrome. Normal function ceases. Aging accelerates. Diabetes develops. Heart attacks strike. The brain degenerates. Life ends early. And it’s all driven, in this understanding, by chronic, low-grade inflammation.

    Where does the perceived threat come from—all that inflammation? Some ingested fats are directly inflammatory. And dumping a huge amount of calories into the bloodstream from any source, be it fat or sugar, may overwhelm and inflame cells. But another source of inflammation is hidden in plain sight, the 100 trillion microbes inhabiting your gut. Junk food, it turns out, may not kill us entirely directly, but rather by prompting the collapse of an ancient and mutually beneficial symbiosis, and turning a once cooperative relationship adversarial.

    We’re already familiar with a version of this dynamic: cavities. Tooth decay is as old as teeth, but it intensified with increased consumption of refined carbohydrates, like sugar, just before and during the industrial revolution. Before cheap sugar became widely available, plaque microbes probably occupied the warm and inviting ecological niche of your mouth more peaceably. But dump a load of sugar on them, and certain species expand exponentially. Their by-product—acid—which, in normal amounts, protects you from foreign bacteria—now corrodes your teeth. A once cooperative relationship becomes antagonistic.

    Something similar may occur with our gut microbes when they’re exposed to the highly refined, sweet, and greasy junk-food diet. They may turn against us.
    A DECADE AGO, microbiologists at Washington University in St. Louis noticed that mice raised without any microbes, in plastic bubbles with positive air pressure, could gorge on food without developing metabolic syndrome or growing obese. But when colonized with their native microbes, these mice quickly became insulin resistant and grew fat, all while eating less food than their germ-free counterparts.

    The researchers surmised that the microbes helped the rodents harvest energy from food. The mice, which then had more calories than they needed, stored the surplus as fat. But across the Atlantic, Patrice Cani at the Catholic University of Louvain in Brussels, Belgium, suspected that inflammation contributed, and that the inflammation emanated from native microbes.

    To prove the principle, he gave mice a low dose of endotoxin, that molecule that resides in the outer walls of certain bacteria. The mice’s livers became insulin resistant; the mice became obese and developed diabetes. A high-fat diet alone produced the same result: Endotoxin leaked into circulation; inflammation took hold; the mice grew fat and diabetic. Then came the bombshell. The mere addition of soluble plant fibers called oligosaccharides, found in things like bananas, garlic, and asparagus, prevented the entire cascade—no endotoxin, no inflammation, and no diabetes.

    “If we take care of our gut microbiota, it will take care of our health,” says one researcher. “I like to finish my talks with one sentence: ‘In gut we trust.'”

    Oligosaccharides are one form of what’s known as a “prebiotic”: fibers that, because they make it all the way to the colon intact, feed, as it were, the bacteria that live there. One reason we’ve evolved to house microbes at all is because they “digest” these fibers by fermenting them, breaking them down and allowing us to utilize their healthful byproducts, like acetic acid, butyric acid, B vitamins, and vitamin K.

    Cani had essentially arrived at the same place as Dandona with his freshly squeezed orange juice. Only his controlled animal experiments allowed a clearer understanding of the mechanisms. Junk food caused nasty microbes to bloom, and friendly bugs to decline. Permeability of the gut also increased, meaning that microbial byproducts—like that endotoxin—could more easily leak into circulation, and spur inflammation. Simply adding prebiotics enjoyed by a select group of microbes—in this case, Bifidobacteria—kept the gut tightly sealed, preventing the entire cascade. The fortified bacteria acted like crowd-control police, keeping the rest of the microbial mob from storming the barrier.

    “If we take care of our gut microbiota, it will take care of our health,” Cani says. “I like to finish my talks with one sentence: ‘In gut we trust.'”

    So our sweet and greasy diet—almost certainly without evolutionary precedent—doesn’t just kill us directly: It also changes gut permeability and alters the makeup of our microbial organ. Our “friendly” community of microbes becomes unfriendly, even downright pathogenic, leaking noxious byproducts where they don’t belong. H.G. Wells would be proud of this story—the mighty Homo sapiens felled by microscopic life turned toxic by junk food. It’s nothing personal; the bugs that bloom with an energy-dense diet may act in their own self-interest. They want more of that food sweet, fatty food on which they thrive.
    AROUND THE TIME when Paresh Dandona began puzzling over the immune response to a fast-food breakfast, a Chinese microbiologist named Liping Zhao was realizing that he needed to change how he ate, or he might drop dead. He was 44 pounds overweight, his blood pressure was elevated, and his “bad” cholesterol was high.

    He caught wind of the studies at Washington University in St. Louis suggesting that microbes were central to obesity. The research jibed with ancient precepts in Chinese medicine that viewed the gut as central to health. So Zhao decided on a hybridized approach—some 21st-century microbiology topped with traditional Chinese medicine.

    He changed his diet to whole grains, rich in those prebiotic fibers important for beneficial bacteria. And he began regularly consuming two traditional medicinal foods thought to have such properties: bitter melon and Chinese yam.

    Zhao’s blood pressure began normalizing and his “bad” cholesterol declined. Over the course of two years, he lost 44 pounds. He sampled his microbes throughout. As his metabolism normalized, quantities of a bacterium called Faecalibacterium prausnitzii increased in his gut. Was its appearance cause or consequence? Others have observed that this bacterium is absent in people suffering from inflammatory diseases, such as Crohn’s disease, as well as Type 2 diabetes. Scientists at the University of Tokyo have shown that colonizing mice with this bacterium and its relatives—called “Clostridium clusters”—protects them against colitis. But still, evidence of causation was lacking.

    Then one day in 2008, a morbidly obese man walked into Zhao’s lab in China. The 26-year-old was diabetic, inflamed, had high bad cholesterol, and elevated blood sugar. No one in his immediate family was heavy, but he weighed 385 pounds.

    Aided by a high fat diet, the microbe appeared able to hijack the metabolism of both mice and man.

    Zhao noticed something odd about the man’s microbes. Thirty-five percent belonged to a single, endotoxin-producing species called Enterobacter cloacae. So he put the man on a version of his own regimen—whole grains supplemented with other prebiotics. As treatment progressed, the Enterobacter cloacae declined, as did circulating endotoxin and markers of inflammation.

    After 23 weeks, the man had lost 113 pounds. That bacterial bloom had receded to the point of being undetectable. Counts of anti-inflammatory bacteria—microbes that specialize in fermenting nondigestible fibers—had increased. But could Zhao prove that these microbial changes caused anything? After all, the regimen may have simply contained far fewer calories than the patient’s previous diet.

    So Zhao introduced the Enterobacter into mice. They developed endotoxemia, fattened up and became diabetic—but only when eating a high fat diet. Mice colonized with bifidobacteria and fed a high fat diet, meanwhile, remained lean, as did germ-free mice. The enterobacter was evidently unique, an opportunist. Aided by a high fat diet, the microbe appeared able to hijack the metabolism of both mice and man.

    Zhao, who related his own story to Science last year, has repeated a version of this regimen in at least 90 subjects, achieved similar improvements, and has more than 1,000 patients in ongoing trials. He declined to be interviewed for this article, saying that the response to his research, both by press and individuals seeking advice, had been overwhelming. “I receive too many emails to ask for help but I can not provide much,” he wrote in an email. “I feel very bad about this and would like to concentrate on my research.”

    There’s a flood of what you might call “fecoprospectors” seeking to catalog and preserve microbial diversity before it is lost in the extinction wave sweeping the globe.

    Other researchers have tried an even more radical approach to treating the microbiome: the fecal transplant. It was originally developed to treat the potentially life-threatening gut infection caused by the bacterium Clostridium difficile. Studies so far suggest that it’s 95 percent effective in ousting C. diff. and has no major side effects. “Fecal engraftment” is now being considered a method for rebooting microbiota generally. Scientists at the Academic Medical Center in Amsterdam mixed stool from lean donors with saline solution and, via a tube that passed through the nose, down the throat and past the stomach, introduced the mixture to the small intestine of nine patients with metabolic syndrome. Control subjects received infusions of their own feces.

    Those who received “lean” microbes saw improvements in insulin sensitivity, though they didn’t lose weight and saw the improvements disappear within a year. But Max Nieuwdorp, senior author on the study, aims to conduct the procedure repeatedly to see if the “lean” microbes will stick. And when he’s identified which are important, he hopes to create an anti-obesity “probiotic” to be taken orally.

    Probiotics are just bacteria thought to be beneficial, like the lactobacilli and other bacteria in some yogurts. In the future probiotics might be bacteria derived from those found in Amazonian Indians, rural Africans, even the Amish—people, in other words, who retain a microbial diversity that the rest of us may have lost. Already, the literature suggests that a gold rush has begun—a flood of what you might call “fecoprospectors” seeking to catalog and preserve the diversity and richness of the ancestral microbiota before it is lost in the extinction wave sweeping the globe.

    Ultimately, the strongest evidence to support microbial involvement in obesity may come from a procedure that, on the face of it, has nothing to do with microbes: gastric bypass surgery. The surgery, which involves creating a detour around the stomach, is the most effective intervention for morbid obesity—far more effective than dieting.

    Originally, scientists thought it worked by limiting food consumption. But it’s increasingly obvious that’s not how the procedure works. The surgery somehow changes expression of thousands of genes in organs throughout the body, resetting the entire metabolism. In March, Lee Kaplan, director of the Massachusetts General Hospital Weight Center in Boston, published a study in Science Translational Medicine showing a substantial microbial contribution to that resetting.

    He began with three sets obese mice, all on a high-fat diet. The first set received a sham operation—an incision in the intestine that didn’t really change much, but was meant to control for the possibility that trauma alone could cause weight loss. These mice then resumed their high fat diet. A second set also received a sham operation, but was put on a calorically restricted diet. The third group received gastric bypass surgery, but was then allowed to eat as it pleased.

    As expected, both the bypass mice and dieted mice lost weight. But only the bypass mice showed normalization of insulin and glucose levels. Without that normalization, says Kaplan, mice and people alike inevitably regain lost weight.

    “I won’t argue that all the effects of the gastric bypass can be transferred by the microbiota. What we’ve found is the first evidence that any can.”

    To test the microbial contribution to these outcomes, Kaplan transplanted the microbiota from each set to germ-free mice. Only rodents colonized with microbes from the bypass mice lost weight, while actually eating more than mice colonized with microbes from the other groups.

    In humans, some studies show a rebound of anti-inflammatory bacteria after gastric-bypass surgery. Dandona has also noted a decline in circulating endotoxin after the procedure. “I would never argue, and won’t argue, that all the effects of the gastric bypass can be transferred by the microbiota,” says Kaplan. “What we’ve found is the first evidence that any can. And these ‘any’ are pretty impressive.” If we understand the mechanism by which the microbiota shifts, he says, perhaps we can induce the changes without surgery.
    NOW, NOT EVERYONE ACCEPTS that inflammation drives metabolic syndrome and obesity. And even among the idea’s proponents, no one claims that all inflammation emanates from the microbiota. Moreover, if you accept that inflammation contributes to obesity, then you’re obligated to consider all the many ways to become inflamed. The odd thing is, many of them are already implicated in obesity.

    Particulate pollution from tailpipes and factories, linked to asthma, heart disease, and obesity, is known to be a cause of inflammation. So is chronic stress. And risk factors may interact with each other: In macaque troops, the high-ranking females, which experience less stress, can eat more junk food without developing metabolic syndrome than the more stressed, lower-ranking females. Epidemiologists have made similar observations in humans. Poorer people suffer the consequences of lousy dietary habits more than do those who are wealthier. The scientists who study this phenomenon call it “status syndrome.”

    Exercise, meanwhile, is anti-inflammatory, which may explain why a brisk walk can immediately improve insulin sensitivity. Exercise may also fortify healthy brown fat, which burns off calories rather than storing them, like white fat does. This relationship may explain how physical activity really helps us lose weight. Yes, exercise burns calories, but the amount is often trivial. Just compensating for that bagel you ate for breakfast—roughly 290 calories—requires a 20-minute jog. And that’s not counting any cream cheese. Sleep deprivation may have the opposite effect, favoring white fat over brown, and altering the metabolism.

    Brain inflammation precedes weight gain, suggesting that the injury might cause, or at least contribute to, obesity.

    Then there’s the brain. Michael Schwartzdirector of the Diabetes and Obesity Center of Excellence at the University of Washington in Seattle, has found that the appetite regulation center of the brain—the hypothalamus—is often inflamed and damaged in obese people. He can reproduce this damage by feeding mice a high-fat diet; chronic consumption of junk food, it seems, injures this region of the brain. Crucially, the brain inflammation precedes weight gain, suggesting that the injury might cause, or at least contribute to, obesity. In other words, by melting down our appetite control centers, junk food may accelerate its own consumption, sending us into a kind of vicious cycle where we consume more of the poison wreaking havoc on our physiology.

    Of course there’s a genetic contribution to obesity. But even here, inflammation rears its head. Some studies suggest that gene variants that increase aspects of immune firepower are over-represented among obese individuals. In past environments, these genes probably helped us fight off infections. In the context of today’s diet, however, they may increase the risk of metabolic syndrome.

    Whether inflammation drives obesity or just contributes, how much of it emanates from our microbiota, or even whether it causes weight gain, or results from it—these are still somewhat open questions. But it is clear that chronic, low-grade inflammation, wherever it comes from, is unhealthy. And as Dandona discovered all those years ago, food can be either pro- or anti-inflammatory. Which brings us back to the question: What should we eat?
    FIFTY YEARS AGO, due to the perceived link with heart disease, nutritionists cautioned against consuming animal fats and recommended hydrogenated vegetable oils, such as margarine, instead. Alas, it turned out that these fats may encourage the formation of arterial plaques, while some fats that were discarded—in fish and olive oil, for example—seem to prevent cardiovascular disease and obesity.

    As people unwittingly cut out healthy fats, they compensated by consuming more sugar and other refined carbohydrates. But a high-sugar diet can produce endotoxemia, fatty liver, and metabolic syndrome in animals. So that’s yet another reason to avoid refined, sugary foods.

    What about popular weight loss regimes, like the Atkins diet, that emphasize protein? In a 2011 study by scientists at the University of Aberdeen, in Scotland, 17 obese men were given a high-protein, low-carb diet. It prompted a decline of anti-inflammatory microbes, whose fermentation byproducts are critical to colonic health, and produced a microbial profile associated with colon cancer. So although it may prompt rapid weight loss, a high-protein, low-carb diet may predispose people to colon cancer. In the rodent version of this experiment, the addition of a prebiotic starch blunted the carcinogenic effect. Again, it’s not only what’s present in your diet that matters, but also what’s absent.

    So, should we sprinkle a packet of fiber on our cheeseburger? Dandona has looked at this possibility and says that though this study has not yet been published, he’s found that packeted fiber does, when eaten with a fast-food meal, soften the food’s inflammatory effects. Fast-food companies could, in theory, pack their buns full of prebiotics, shielding their customers somewhat from metabolic syndrome.

    But that’s not really what Dandona or anyone else is advocating. The pill approach—the idea that we can capture a cure in a gel cap—may be part of what got us in trouble to begin with. Natural variety and complexity have their own value, both for our own bodies and for our microbes. This may explain why orange juice, which contains plenty of sugur, doesn’t have inflammatory effects while a calorically equivalent quantity of sugar water does. Flavonoids, other phytochemicals, vitamins, the small amount of fiber it carries, and other things we have yet to quantify may all be protective.

    Fast-food companies could, in theory, pack their buns full of prebiotics, shielding their customers somewhat from metabolic syndrome.

    To that end, consider a study by Jens Walter (PDF), a scientist at the University of Nebraska-Lincoln. He supplemented the diet of 28 volunteers with either brown rice, barley, or both. Otherwise, they continued eating their usual fare. After four weeks, those who consumed both grains saw increased counts of anti-inflammatory bacteria, improved insulin sensitivity, and reduced inflammation—more so than subjects who just had one grain. Walter doesn’t think it’s an accident that those who ate both barley and brown rice saw the greatest improvement. The combination likely presented microbes with the largest array of fermentable fibers.

    Scientists are also intensely interested in concocting “synbiotics,” a mixture of probiotic bacteria and the prebiotic fibers that feed them. This type of combination may already exist in staple dishes and garnishes, from sauerkraut to kefir, in traditional cuisines the world over.  In theory, such unpasteurized, fermented foods that retain their microbial communities are a health-producing triple whammy, containing prebiotic fibers, probiotic bacteria, and healthful fermentation byproducts like vitimins B and K. A smattering of recent studies suggest that embracing such grub could protect against metabolic syndrome. In one monthlong trial on 22 overweight South Koreans, unpasteurized fermented kimchi, which is made from cabbage, improved markers of inflammation and caused very minor decreases in body fat. Fresh, unfermented kimchi also helped, but not as much. In another double-blind, placebo-controlled study on 30 South Koreans, a pill of fermented soybean paste eaten daily for 12 weeks decreased that deadly visceral fat by 5 percent. Triglycerides, a risk factor for heart attacks, also declined. An epidemiological study, meanwhile, found that consumption of rice and kimchi cut the odds of metabolic syndrome. It all hints at a future where sauerkraut, kimchi, sour pickles, and other fermented foods that contain live microbial cultures do double duty as anti-obesity medicine.

    So what else to eat? Onions and garlic are especially rich in the prebiotic fiber inulin, which selectively feeds good bacteria within. Potatoes, bananas, and yams carry loads of digestion-resistant starches. Apples and oranges carry a healthy serving of polysaccharides (another form of prebiotic). Nuts and whole grains do as well. Don’t forget your cruciferous vegetables (cabbage, broccoli, and cauliflower) and legumes. There’s no magic vegetable. Yes, some plant products are extra rich in prebiotics—the Jerusalem artichoke, for example—but really, these fibers abound in plants generally, and for a simple reason: Plants store energy in them. That’s why they’re resistant to degradation. They’re designed to last. (For more on what foods to eat, see “Should I Take A Probiotic?“)

    The very qualities that improve palatability and lengthen shelf life—high sugar content, fats that resist turning rancid, and a lack of organic complexity—make refined foods toxic to your key microbes. Biologically simple, processed foods may cultivate a toxic microbial community, not unlike the algal blooms that result in oceanic “dead zones.”

    In fact, scientists really do observe a dead zone of sorts when they peer into the obese microbiota. Microbes naturally form communities. In obese people, not only are anti-inflammatory microbes relatively scarce, diversity in general is depleted, and community structure degraded. Microbes that, in ecological parlance, we might call weedy species—the rats and cockroaches of your inner world—scurry around unimpeded. What’s the lesson? Junk food may produce a kind of microbial anarchy. Opportunists flourish as the greater structure collapses. Cooperative members get pushed aside. And you, who both contain and depend on the entire ecosystem, pay the price.

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    Can Endurance Sports Really Cause Harm? The Lipopolysaccharides of Endotoxemia and Their Effect on the Heart

    January 17th, 2016

    Also See:
    Endotoxin: Poisoning from the Inside Out
    Ray Peat, PhD on Endotoxin
    Exercise Induced Stress
    Stress — A Shifting of Resources
    Exercise and Endotoxemia
    Carbohydrate Lowers Exercise Induced Stress
    Low carb + intensive training = fall in testosterone levels
    Exercise and Effect on Thyroid Hormone
    Exercise Induced Menstrual Disorders
    Ray Peat, PhD: Quotes Relating to Exercise
    Ray Peat, PhD and Concentric Exercise
    Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise
    Running on Empty
    How does estrogen enhance endotoxin toxicity? Let me count the ways.
    Bowel Toxins Accelerate Aging
    Ray Peat, PhD on the Benefits of the Raw Carrot
    Protection from Endotoxin
    Endotoxin-lipoprotein Hypothesis
    Protective Bamboo Shoots
    The effect of raw carrot on serum lipids and colon function
    Are Happy Gut Bacteria Key to Weight Loss?


    (I personally don’t agree with the treatment options listed, but the actions of LPS during stress and exercise are valid and worthy of your time especially considering the exercise world’s complete ignorance of the topic. -FPS)

    by Gary Huber, DO, AOBEM

    The endurance athlete is viewed as a model of aerobic efficiency, possessing tremendous cardiovascular health. Certainly we can agree that exercise induces a great number of benefits to our physiology and greatly improves the quality of life, but evidence exists that excessive exercise can cause cardiovascular damage. The heavy endurance athletes such as triathletes, marathon runners, and cyclists spend hours upon hours in a state of physiologic stress. Was the human body truly built to withstand this repetitive high oxidative stress exposure? There is literature to suggest that for some, the damage caused by ischemia to the bowel and the resultant endotoxemia leads to vascular and myocardial damage that in fact increases the risk for arrhythmic and atherosclerotic change. This article is written by an endurance sport enthusiast, so it is not intended to derail such activities but rather to explore this issue of lipopolysaccharides (LPS) and the cardiac damage that occurs so that we can ascertain the true risk involved and explore options for avoidance.

    In a US population of more than 300 million people, 350,000 sudden cardiac deaths, or 111 events per 100,000 people, occur annually. Within this population, we understand that risk is secondary to lifestyle, age, and a host of other factors such as the building inflammation that often accompanies poor lifestyle and dietary decisions. But in a youthful age group who is exercising, we don’t expect sudden cardiac deaths. We have all heard tragic stories of the young athlete who dies on the field only to discover that he had an undiagnosed valvular or vascular defect. But there are a significant number of cases in which no identifiable anatomical defect can be found, yet the cause of death is listed as cardiac in nature. In a well-known study by Harmon published in 2011 in the journal Circulation, they reported a sudden cardiac death rate of NCAA athletes of 1 per 44,000 annually, or roughly 2.3/100,000.1 This might seem high, given that we are speaking of young athletes; but a look at CDC population-based data shows that cardiac-related death in the general population aged 15 to 24 is 2.5 per 100,000 people.2-5

    One of the problems with the Harmon study is that the researchers did not document autopsy findings, and we are left to guess at the actual cause of cardiac death. This problem appears to be related to increased intensity of training, as the death rate is increased 2-fold from high school athletes to those on college teams.6,7

    A 25-year review of autopsies in military recruits by Eckart showed a higher than expected rate of nontraumatic death at 13 per 100,000 recruits per year.8 86% of these deaths were related to exercise. Of those determined to be cardiac in origin, 61% were secondary to coronary artery pathology. The surprising finding is that despite autopsy, 35% of deaths determined to be nontraumatic sudden death were idiopathic. Another 20% of the cardiac deaths were diagnosed as myocarditis. Is it possible that the physical demand of these recruits played a role in the idiopathic and myocarditis deaths? That is an issue worth exploring through the lens of endotoxemia.

    It has been demonstrated that LPS from gram-negative bacteria adversely affects cardiomyocytes, leading to apoptotic cell death.9-12 It is this apoptotic cell death that directly contributes to other forms of heart failures such as myocarditis, congestive heart disease, diabetic cardiomyopathy, chronic pressure overload, and ischemia-reperfusion injury.13-21 So as we view the myocarditis, arrhythmic, and other cardiovascular deaths in athletes, we have to ask, is it possible that the very activities which we love – our endurance sports – are acting as the nidus for LPS toxicity that is poisoning our hearts?

    Defining the Problem
    Engaging in prolonged endurance training or endurance events creates multiple physiologic stressors to alter our physiology. Blood flow must be redirected from central gut and liver to the peripheral muscle mass as well as the skin to facilitate heat release. This leads to a relative bowel ischemia as the splanchnic blood flow is reduced by 80%.22-24 Further exacerbating this ischemia is the simple volume loss due to sweat, the mechanical damage from the microtrauma of running, as well as thermal insult from rising body temperatures that all combine to worsen the mucosal damage occurring in the gut lining.25,26 This shock-induced damage results in loss of intestinal wall integrity and death to gram-negative organisms. The cell walls of gram-negative bacteria are composed of LPS, also known as endotoxins. LPS comprise 75% of the cell walls of gram-negative bacteria, and a single gram-negative bacterial cell wall can release 1 million LPS molecules into circulation.27,28

    Excessive release of LPS secondary to bowel ischemia and loss of barrier effect can overwhelm the portal circulation and the Kupffer cells’ ability to neutralize them, resulting in entry to the general circulation where they cause significant adverse symptoms. The intestinal permeability induced by these sporting activities is thought to explain the high rate of occurrence of GI complaints such as diarrhea, cramps, and vomiting.29-31 The occurrence of GI issues has been reported to range from 30% to 93% of all endurance athletes and represents a common problem that is often unrecognized as a serious sign of endotoxemia. Recall that LPS endotoxemia is the process of sepsis, so other sepsislike symptoms may emerge, including fever, shivering, headache, and muscle ache.32-38

    Endurance training clearly taxes liver function, as demonstrated by the Moncada-Jimènez study wherein endurance athletes completing a duathlon demonstrated endotoxemia in 50% of participants.39 Beyond that, all participants showed an increase in both AST and ALT level after their event. This reflects that during periods of endurance training, the reduction in splanchnic blood flow leading to bacterial death and translocation across the intestinal wall enter the portal circulation to reach the liver and induce the acute phase response. This same finding has been demonstrated in all types of endurance sport athletes, including cyclists, marathoners, and others.40-42

    Sepsis represents our best understanding of endotoxins. Patients with sepsis experience fever, dizziness, GI complaints, shivering, and cardiovascular collapse secondary to the LPS presence in the bloodstream. I would contend that if you have ever watched someone finish a marathon, the temperature regulation issues, the gut effects, the shivering, and other symptoms that occur are just a milder version of sepsis. The mechanism is the same, and unfortunately the cardiovascular risk is a part of this picture. Yes, endurance athletes are jeopardizing their heart health and potentially causing heart damage every time they train and compete. Their cardiovascular efficiency may be enhanced, but the LPS release is causing myocyte damage.

    LPS can cause direct stimulation of cytokines, including TNF-alpha, which leads to severe problems; but low levels of LPS can cause damaging effects without the stimulation of cytokines. There is a multilevel response potential such that low levels of circulating LPS can cause cardiac apoptosis without stimulating excess cytokine response. It has a direct toxicity beyond its cytokine effect by directly engaging the myocyte via the toll-like receptor-4 (TLR-4).43 Low levels in the nanogram-per-milliliter range can alter myocyte function.44,45

    LPS can stimulate cardiac myocytes to release TNF-alpha and nitric oxide to induce apoptosis via an autocrine manner, but this level of damage occurs in the microgram/ml range. LPS at low levels does not rely on NO or TNF-alpha to cause apoptosis.46-49

    So LPS exposure, whether high dose in micrograms or low dose in nanograms, has multiple mechanisms of action to induce cardiac damage. LPS in low doses (10 ng/ml) decreased the ratio of the antiapoptotic protein Bcl-2 relative to the proapoptotic protein Bax, thus influencing apoptosis. The Li study showed that in vivo use of LPS in low dose caused a 2-fold increase in apoptosis that was blocked by the use of losartan.50 The ability of LPS to independently induce apoptosis outside cytokine contribution is via stimulation of cardiac AT1 receptors. Angiotensin II induces caspase-3 enzymes which trigger apoptosis.51,52 A single low dose of LPS that caused no appreciable distress and no adverse impact on blood pressure was sufficient to increase cardiac apoptosis. Low levels of LPS have been shown to be clinically relevant in multiple disease processes without causing overt distress or blood pressure changes.53-55

    In the Jeukendrup study, 29 triathletes were followed with blood test before and after an Ironman distance triathlon, and a full 93% reported GI issues; 68% had endotoxemia defined as LPS levels >5 pg/ml.56 Other measures of note were IL-6 levels elevated 27-fold and CRP increased 20-fold. Interestingly, this study followed these athletes with blood measures 16 hours after the race and found that the rate of endotoxemia had increased from 68% to 79% at the 16-hour mark, demonstrating the extended effect of such physical efforts. The prealbumin level was reduced by 12%, consistent with acute phase reactions wherein the body directs efforts in making CRP and fibrinogen at the expense of making albumin and prealbumin. This is expected in the face of high CRP which was documented. In another extreme endurance event, Brocke-Utne demonstrated an endotoxemia occurrence rate of 81%.57

    A Look at the Cellular Mechanism of Endotoxemia
    LPS in the circulation binds LBP (lipopolysaccharide binding protein) to form a complex LPS-LBP which binds to the cell membrane of Kupffer cells, reacting with the TLR-4 receptor and triggering the activation and translocation of NF-kB.58,59 So both the endotoxin and the oxidative stress of intense sporting activity induce production of NF-kB, thus upregulating pro-inflammatory cytokines.

    LPS release causes activation of the coagulation and the complement cascade.

    The pathway for this activity is through the toll-like receptor 4 (TLR-4). Cardiac myocytes express TLR-4 receptors and are susceptible to direct damage by LPS exposure.44,45,60,61

    LPS stimulation of TLR-4 receptors causes depression of the myocyte contractility; they impair beta-adrenergic reactivity, and induce apoptosis through the cardiac renin-angiotensin system and the angiotensin type 1 receptors. This stimulation can lead to cardiac fibrosis.9-12, 62-66

    In studies by Lew et al. in 2013, researchers exposed mice to low levels of LPS that caused no discernible clinical adverse events and yet with chronic exposure demonstrated development of fibrosis and increased mortality.66 Lew et al. found that the use of losartan, which had previously been shown effective in Li’s study, had no effect in their mouse model.

    Mechanisms for LPS exposure include67-70:
    1. sports, endurance activity, strenuous exercise
    2. high-fat meals
    3. periodontal disease
    4. chronic type 2 diabetes
    5. smoking
    6. chronic infections, URIs, etc.
    7. metabolic syndrome
    8. cirrhosis
    9. heart failure

    These can cause levels of LPS in the picogram to nanogram/ml range.71

    Chronic recurrent exposure of LPS by athletes can be compared to the low chronic levels of exposure seen with people with periodontal disease, smokers, chronic infections, or chronic heart failure.72 These low levels of LPS are seen in humans with chronic heart failure, suggesting a slow destructive apoptotic occurrence.

    This is eerie with relation to the NCAA athletes or the military recruit studies. In Lew’s study, the mice received low doses of LPS on a weekly basis, showing mild transient effects that resolved within hours. Sounds like symptoms associated with doing a hard interval workout or a long training ride. The LPS-treated mice appeared normal, with good activity and normal hemodynamic measures, including normal LV size and function, but then over time demonstrated an increased mortality with unexpected deaths. This sounds like endurance training with weekly doses of hard efforts that release LPS, causing transient symptoms and low-IgG anti-LPS levels, while causing cardiac fibrosis and apoptosis, resulting in an increased risk for sudden cardiac death which has been documented.

    Short-term benefits may be seen with our innate immune response to transient inflammation. Mann’s experiments, which employed a short-term preload with LPS, demonstrated a protective effect, similar to the concept of hormesis.73 But he went on to report that the chronic nature of the inflammatory process of repeated LPS exposure is damaging, leading to atherosclerosis. The recurrent activation of TLR-4 is damaging to cardiovascular health and produces fibrosis of the myocyte.

    LPS is involved in plaque rupture and vascular signaling. TLR-4 is upregulated and concentrated in the shoulder region of plaque, which is where rupture most commonly occurs. There is a clear association between bacterial infection and, in the case of our endurance athletes, chronic bacterial LPS exposure and the development of atherosclerosis. TLR-4-induced inflammation has been linked to plaque instability, and potential for acute coronary syndrome.73

    The review by Venardos discusses the importance of myocardial antioxidant enzyme systems such as the glutathione peroxidase (GPX) and the thioredoxin reductase (TxnRed) system and their important role against oxidative stress and recovery in cardiac tissue.20 The GPX and TxnRed are both selenocysteine-dependent enzymes. The sweat losses of all minerals, not the least of which are selenium, iodine, and magnesium, play a role in elevating risk; and their absence reduces myocytes’ ability to withstand oxidative challenges.

    Defining Endotoxemia in Various Reports
    Endotoxemia is defined as an LPS level greater than 5 pg/ml. In reviewing this literature, various definitions have been employed as well as various tests and reagents to identify it; and as such, several factors need to be taken into consideration. Depending on the reagent used and whether methods to remove LPS inhibitory substances are used, the level can vary widely. For example some reagents used to measure LPS are also sensitive to B-glucan from fungi, so use of this type of test will yield higher levels of LPS being reported. These are the factors that create confusion when comparing studies but the evidence is still greatly significant in well-controlled studies using proper reagents that LPS is real and problematic.

    Chronic effect of LPS exposure
    Anti-LPS antibodies are produced by the body to bind LPS when present. These levels are lower in endurance athletes both before and after endurance events and thought to represent the chronic low levels of LPS occurring in these athletes from regular training resulting in “drainage” of adequate levels of IgG anti-LPS.74,75

    There is chronic leakage of LPS secondary to long-term mucosal damage and recurrent efforts leading to low IgG anti-LPS and thus the suspicion of chronic cardiac exposure to LPS and myocyte damage. The fact that TNF-alpha may not be detected in the blood is not a surprise, as TNF-alpha has a very short half-life, and even in patients with documented sepsis, the presence of TNF is typically only found in 4% to 54% of patients.76

    We know that endurance athletes struggle with frequent upper respiratory tract infections (URI) secondary to the immune suppressive effect of their sport.77 Immune suppression after extreme efforts has been documented to last for 3 to 72 hours post exertion.78 The stress incurred by the HPA axis and all of the resultant immune and cytokine reactions result in a decline in the IgA levels, leaving the gut unprotected and vulnerable to barrier defects.78 The simple application of vitamin C has been shown to reduce URI frequency post endurance events.79

    As stated in the opening of this article, the goal is not to condemn endurance sports but rather understand the potential risk of damage of such activity and proceed in a manner that not only ensures greater health but likely improves athletic performance as well. There are several well-studied approaches that offer promise as well as safety in their application.

    Resveratrol suppresses endotoxin-induced production of pro-inflammatory cytokines and activates the Nrf2 antioxidant defense pathway in vivo. Classic elevation in creatine kinase (CK) and lactate dehydrogenase (LDH) is seen with cardiac damage secondary to exposure to LPS. Hao, employing an in vivo mouse study, demonstrated that pretreatment with resveratrol significantly reduced LPS-induced elevation in CK and LDH.80 Echocardiogram demonstrated a preservation of ejection fraction that had previously been reduced in the face of LPS administration. These investigators further pursued this topic by culturing human cells in LPS with resveratrol and demonstrated a significant reduction in apoptosis and necrosis in the resveratrol cultured cells.

    Vitamin C reduces bacterial overgrowth, and endotoxemia, and reduces the intestinal barrier defect. Vitamin C in doses of just 1000 mg prior to a significant training effort has been shown to be effective in producing a protective antioxidant effect, maintains the gut barrier effect, and reduces LPS leakage into the circulation.81

    Patients with IBD, a common condition found in endurance athletes, show significantly reduced levels of vitamin C in mucosal tissue compared with non-IBD controls.82 The study by Abhilash showed that vitamin C improved the integrity of mucosal tissue, reduced damage from LPS, protecting the liver and reducing fibrosis secondary to oxidative insult.83

    Lactobacillus plantarum produces lipoteichoic acid (LTA), which has been shown to reduce LPS-induced TNF-alpha expression and downregulate the TLR-4 activity.84,85 The goal with this type of treatment is to produce tolerance against the effects of LPS. Reducing the acute LPS effect may translate into reduction of the cumulative cardiovascular damage long term.

    Curcumin has been employed for a multitude of benefits related to reduction in inflammation. Its use in the treatment of inflammatory bowel disease and inhibition of ulcer formation has been well studied and documented. Constituents of curcumin have a protective effect and inhibit intestinal spasm while increasing gastrin, secretin, bicarbonate, pancreatic enzyme, and mucous secretion.86

    Turmeric’s anti-inflammatory activity may lead to improvement in obesity and obesity-related diseases such as heart disease and diabetes. Curcumin interacts with hepatic stellate cells and macrophages, wherein it suppresses several cellular proteins such as transcription factor NF-kB and STAT-3, and activates Nrf2 cell signaling pathway.87

    In a 2009 study, curcumin was used to block the muscle-wasting effects of LPS.88 There was a dose dependent reduction in muscle loss in mice injected with LPS. Curcumin inhibited p38 kinase activity (involved in stress-induced apoptosis) in LPS-affected muscle.89 Knowing the muscle-wasting effects of endurance sports in conjunction with the known release of LPS, curcumin would seem a safe and natural approach for reduction of oxidative stress and preservation of bowel function and integrity.

    One last variable needs consideration in this topic. Chagnon cited evidence in 2005 of a cardiac-derived myocardial depressant factor known as macrophage migration inhibitory factor (MIF).12 It appears that MIF is a critical piece to the mechanism of cardiac damage from LPS, yet its exact mechanism remains unclear. MIF is released from myocardium in response to LPS and acts as an inflammatory mediator, disrupting immune homeostasis. In a mouse study wherein investigators employed an anti-MIF antibody they were able to demonstrate a complete blockade of the LPS effect on myocytes. The blockade of MIF resulted in an increase in Bcl2/Bax ratio (an antiapoptotic result), inhibiting the release of mitochondrial cytochrome c, which in turn prevents caspase 3 activation (another antiapoptotic effect) and reduces DNA fragmentation.

    Given that MIF is in fact an inflammatory mediator in immune homeostasis, it is quite possible that the multidimensional impact of resveratrol, vitamin C, and curcumin is having a direct effect on MIF. Given that these botanicals and nutrients have multiple mechanisms of action, including effects on mitochondrial function, PGC-1a, cyclooxygenase enzymes, NF-kB, and cytokine production, including TNF-alpha, their combined impact may indeed block cardiovascular damage.

    A controlled study to assess the combined impact of these protective elements on endurance athletes will likely never be done; but given the information discussed here, I think that it is more than prudent to share this approach with all endurance athletes, as it represents the potential for reducing sudden cardiac events and promoting greater health overall.

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    Dr. Gary Huber is president of the LaValle metabolic institute. He spent 20 years as an emergency medicine physician before joining Jim LaValle in the practice of integrative medicine at LMI. Dr. Huber is an adjunct professor teaching integrative medicine practice at the University of Cincinnati College of Pharmacy as well as a clinical preceptor for pharmacy students. Dr. Huber also lectures on hormone replacement therapies and integrative care for the American Academy of Anti-Aging Medicine for the University of South Florida. He has developed the Metabolic Code Professional Weight Loss Program that has proved very beneficial in reversing metabolic syndrome issues. Dr. Huber has a long-held interest in nutrition and human physiology as it relates to wellness and longevity. He has served as medical director for the Flying Pig Marathon and is presently on the board of directors for Loveland’s Amazing Race, a local charity event.

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    The Story of an Egg

    January 17th, 2016

    Pasture raised is the term to look for when buying eggs.

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    Joseph Dumit: Maximum Prescriptions: Growing Health and Happiness through Facts and Pharmaceuticals

    January 6th, 2015

    Joe Dumit provides insight into the minds of pharmaceutical companies. Economics, marketing, and medicine are intimately linked. Diseases that offer the highest potential return on investment are researched the most.

    Props to Martin Brown for the find.

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    Common features of stress response

    October 24th, 2014

    Also see:
    Low Blood Sugar Basics
    Stress — A Shifting of Resources
    Ray Peat, PhD on Low Blood Sugar & Stress Reaction
    Belly Fat, Cortisol, and Stress
    Stress, Portrait of a Killer – Full Documentary (2008)
    Stress and Aging: The Glucocorticoid Cascade Hypothesis
    Sugar (Sucrose) Restrains the Stress Response
    W.D. Denckla, A.V. Everitt, Hypophysectomy, & Aging
    Removal of the Pituitary: Slows Aging and Hardening of Collagen


    Common features of stereotypical/non-specific stress response:
    Hypothalamus stimulates pituitary to secrete ACTH
    Secretion of corticoids by adrenal cortex
    Secretion of adrenaline by adrenal medulla
    Adrenal enlargement
    Atrophy of thymus and lymph nodes
    Inhibition of inflammatory reactions
    Production of sugar
    Development of peptic ulcers in stomach and intestines

    From Chapter 1 of “Stress without Distress” by Hans Selye.

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    TNF-alpha, Obesity, Endotoxin, Insulin Resistance, and Diabetes

    October 18th, 2014

    Also see:
    Endotoxin: Poisoning from the Inside Out
    Protection from Endotoxin
    Endotoxin-lipoprotein Hypothesis
    Low Sodium Diet: High FFA, Insulin Resistance
    Aldosterone, Sodium Deficiency, and Insulin Resistance
    The Randle Cycle
    Free Fatty Acids Suppress Cellular Respiration
    Dairy, Calcium, and Weight Management in Adults and Management
    Belly Fat, Cortisol, and Stress
    Stress and Aging: The Glucocorticoid Cascade Hypothesis

    TNF-alpha and insulin resistance:

    Trends Endocrinol Metab. 2000 Aug;11(6):212-7.
    Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes.d
    Moller DE.
    Tumor necrosis factor alpha (TNF-alpha) has well-described effects on lipid metabolism in the context of acute inflammation, as in sepsis. Recently, increased TNF-alpha production has been observed in adipose tissue derived from obese rodents or human subjects and TNF-alpha has been implicated as a causative factor in obesity-associated insulin resistance and the pathogenesis of type 2 diabetes. Thus, current evidence suggests that administration of exogenous TNF-alpha to animals can induce insulin resistance, whereas neutralization of TNF-alpha can improve insulin sensitivity. Importantly, results from knockout mice deficient in TNF-alpha or its receptors have suggested that TNF-alpha has a role in regulating in vivo insulin sensitivity. However, the absence of TNF-alpha action might only partially protect against obesity-induced insulin resistance in mice. Multiple mechanisms have been suggested to account for these metabolic effects of TNF-alpha. These include the downregulation of genes that are required for normal insulin action, direct effects on insulin signaling, induction of elevated free fatty acids via stimulation of lipolysis, and negative regulation of PPAR gamma, an important insulin-sensitizing nuclear receptor. Although current evidence suggests that neutralizing TNF-alpha in type 2 diabetic subjects is not sufficient to cause metabolic improvement, it is still probable that TNF-alpha is a contributing factor in common metabolic disturbances such as insulin resistance and dyslipidemia.

    Nature. 1997 Oct 9;389(6651):610-4.
    Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS.
    Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans and it blocks the action of insulin in cultured cells and whole animals. To investigate the role of TNF-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFalpha-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.

    Nihon Rinsho. 1999 Mar;57(3):622-6.
    [Syndrome X].
    Kotake H, Oikawa S.
    Insulin resistance is an early and major feature in the development of non-insulin-dependent diabetes mellitus (NIDDM). It is also associated with hyperlipidemia, hypertension, obesity and cardiovascular disease. It is the clustor of the risk factors for atherosclerosis and recognized as ‘insulin-resistance syndrome’ (Syndrome X). Central (abdominal) obesity is much more strongly associated with insulin resistance than overall obesity. The increase of both the influx of free fatty acid to liver and the production of TNF-alpha in adipose tissue may play an important role in mechanism of insulin resistance associated with central obesity. Calorie restriction and weight loss improve insulin sensitivity in overweight humans. Exercise training also improves insulin sensitivity via increased oxidative enzymes, glucose transporters (GLUT4) and capillarity in muscle as well as by reducing abdominal fat. The new ‘glitazones’ (thiazolidinediones) is used clinically to improve insulin sensitivity.

    Physiol Res. 1998;47(4):215-25.
    Thiazolidinediones–tools for the research of metabolic syndrome X.
    Komers R, Vrána A.
    “The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity…Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR [insulin resistance].”

    Exp Clin Endocrinol Diabetes. 1999;107(2):119-25.
    Mechanisms of TNF-alpha-induced insulin resistance.
    Hotamisligil GS.
    There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha’s promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.

    TNF-alpha and obesity:

    The Journal of Clinical Endocrinology & Metabolism August 1, 1998 vol. 83 no. 8 2907-2910
    Tumor Necrosis Factor-α in Sera of Obese Patients: Fall with Weight Loss
    Paresh Dandona, Ruth Weinstock, Kuldip Thusu, Ehad Abdel-Rahman, Ahmad Aljada, and Thomas Wadden
    In view of the recent demonstration that obesity in animals and humans is associated with an increase in tumor necrosis factor-α (TNFα) expression, that this expression falls with weight loss, and that TNFα may specifically inhibit insulin action, the possibility that TNFα may be a mediator of insulin resistance has been raised. We have undertaken this study to investigate whether serum TNFα concentrations are elevated in obese subjects, whether they fall after weight loss, and whether this fall parallels the fall in insulin release after glucose challenge. Obese patients (age range: 25–54, weight mean ± sd: 96.4 ± 13.8 kg, body mass index: 35.7 ± 5.6 kg/m2) were started on a diet program. The mean weight fell to 84.5 ± 11.3 (P < 0.0001) and body mass index to 31.3 ± 4.9 (P < 0.0001). Plasma TNFα concentrations were markedly elevated in the obese (3.45 ± 0.16 pg/mL), when compared with controls (0.72 ± 0.28 pg/mL), and fell significantly (2.63 ± 1.40 pg/mL) after weight loss (P < 0.02). The magnitude of insulin release after glucose (75 g) challenge (area under the curve) also fell significantly (P < 0.01) after weight loss. The magnitude of weight loss and fall in TNFα were related to basal body weight (r = 0.57, P < 0.001) and basal TNFα (r = 0.55, P < 0.001) concentrations, respectively, but not to each other or to the glucose-induced insulin release (area under the curve). We conclude that obesity is associated with increased plasma TNFα concentrations, which fall with weight loss. Because circulating TNFα may mediate insulin resistance in the obese, a fall in TNFα concentrations may contribute to the restoration of insulin resistance after weight loss, Thus, TNFα may be an important circulating cytokine, which may provide a potentially reversible mechanism for mediating insulin resistance.

    Endotoxin Increases TNF-alpha, Associated with Insulin Resistance and Diabetes:

    Diabetes Care February 2011 vol. 34 no. 2 392-397
    Endotoxemia Is Associated With an Increased Risk of Incident Diabetes
    Pirkko J. Pussinen, PHD1, Aki S. Havulinna, MSC2, Markku Lehto, PHD3,4, Jouko Sundvall, MSC2 and Veikko Salomaa, MD2
    OBJECTIVE Diabetes is accompanied with a chronic low-grade inflammation, which may in part be mediated by endotoxins derived from Gram-negative bacteria.
    RESEARCH DESIGN AND METHODS We investigated in a population-based cohort whether endotoxemia is associated with clinically incident diabetes. The serum endotoxin activity was measured by limulus assay from the FINRISK97 cohort comprising 7,169 subjects aged 25–74 years and followed up for 10 years.
    RESULTS Both the subjects with prevalent diabetes (n = 537) and those with incident diabetes (n = 462) had higher endotoxin activity than the nondiabetic individuals (P < 0.001). The endotoxin activity was significantly associated with increased risk for incident diabetes with a hazard ratio 1.004 (95% CI 1.001–1.007; P = 0.019) per unit increase resulting in a 52% increased risk (P = 0.013) in the highest quartile compared with the lowest one. The association was independent of diabetes risk factors: serum lipids, γ-glutamyl transferase, C-reactive protein, BMI, and blood glucose. Furthermore, the association of endotoxemia with an increased risk of incident diabetes was independent of the metabolic syndrome as defined either by the National Cholesterol Educational Program-Adult Treatment Panel III or the International Diabetes Federation. Endotoxin activity was linearly related (P < 0.001) to the number of components of the metabolic syndrome.
    CONCLUSIONS Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes.

    Diabetes Care. 2011 Feb;34(2):392-7.
    Endotoxemia is associated with an increased risk of incident diabetes.
    Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V.
    Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes.

    Diabetes. 2007;56(7):1161-1772.
    Metabolic Endotoxemia Initiates Obesity and Insulin Resistance
    Patrice D. Cani; Jacques Amar; Miguel Angel Iglesias; Marjorie Poggi; Claude Knauf; Delphine Bastelica; Audrey M. Neyrinck; Francesca Fava; Kieran M. Tuohy; Chantal Chabo; Aurélie Waget; Evelyne Delmée; Béatrice Cousin; Thierry Sulpice; Bernard Chamontin; Jean Ferrières; Jean-François Tanti; Glenn R. Gibson; Louis Casteilla; Nathalie M. Delzenne; Marie Christine Alessi; Rémy Burcelin
    Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.

    Saturated fats reduce endotoxemia, lipid peroxidation, and TNF-alpha:

    Hepatology. 1997 Dec;26(6):1538-45.
    Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat.
    Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.
    We investigated the potential of dietary saturated fatty acids to decrease endotoxemia and suppress expression of cyclooxygenase 2 (Cox-2) and tumor necrosis factor alpha (TNF-alpha) in established alcohol-induced liver injury. Six groups (five rats/group) of male Wistar rats were studied. Rats in group 1 were fed a fish oil-ethanol diet for 6 weeks. Rats in groups 2, 3, and 4 were fed fish oil and ethanol for 6 weeks. Ethanol administration was stopped at this time, and the rats were switched to isocaloric diets containing dextrose with fish oil (group 2), palm oil (group 3), or medium-chain triglycerides (group 4) as the source of fat for an additional 2 weeks. Rats in groups 5 and 6 were fed fish oil-ethanol and fish oil-dextrose, respectively, for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, and levels of messenger RNA (mRNA) for Cox-2 and TNF-alpha. Concentrations of endotoxin were determined in plasma. The most severe inflammation and fibrosis were detected in groups 1 and 5, as were the highest levels of endotoxin, lipid peroxidation, and mRNA for Cox-2 and TNF-alpha. After ethanol was discontinued, there was minimal histological improvement in group 2 but near normalization of the histology, including regression of fibrosis, in groups 3 and 4. Histological improvement was associated with decreased levels of endotoxin, lipid peroxidation, and reduced expression of Cox-2 and TNF-alpha. The data indicate that a diet enriched in saturated fatty acids (groups 3 and 4) effectively reverses alcohol-induced liver injury, including fibrosis. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased levels of TNF-alpha and Cox-2.

    Lipoproteins protect against endotoxemia and TNF-alpha:

    Eur Heart J. 1993 Dec;14 Suppl K:125-9.
    The protective effect of serum lipoproteins against bacterial lipopolysaccharide.
    Read TE, Harris HW, Grunfeld C, Feingold KR, Kane JP, Rapp JH.
    Lipoproteins bind and inactivate bacterial endotoxin, both in vitro and in vivo. Both cholesterol ester-rich and TG-rich lipoproteins, and TG-rich lipid emulsions can prevent death in mice when pre-incubated with a lethal dose of endotoxin before intraperitoneal administration. Chylomicrons can also prevent death when given intravenously after endotoxin in rats. The metabolic fate of lipoprotein-bound endotoxin appears to be directed by the lipoprotein particle. When administered with chylomicrons, the plasma clearance and hepatic uptake of endotoxin are enhanced. Endotoxin is shunted preferentially to hepatocytes and away from hepatic macrophages, thereby increasing endotoxin excretion [corrected] in bile. The survival benefit and alterations in metabolism afforded by chylomicrons correlate with a reduction in peak serum levels of tumour necrosis factor (TNF), providing a possible mechanism by which lipoproteins protect against endotoxin-induced death. These findings suggest a possible role for lipoproteins or lipid emulsions in the body’s defence against endotoxaemia.

    Dairy lowers TNF-alpha in the overweight:

    Am J Clin Nutr January 2010 vol. 91 no. 1 16-22
    Effects of dairy compared with soy on oxidative and inflammatory stress in overweight and obese subjects
    Michael B Zemel, Xiaocun Sun, Teresa Sobhani, and Beth Wilson
    Background: We recently showed that calcitriol increases oxidative and inflammatory stress; moreover, inhibition of calcitriol with high-calcium diets decreased both adipose tissue and systemic oxidative and inflammatory stress in obese mice, whereas dairy exerted a greater effect. However, these findings may be confounded by concomitant changes in adiposity.
    Objective: The objective of this study was to evaluate the acute effects of a dairy-rich diet on oxidative and inflammatory stress in overweight and obese subjects in the absence of adiposity changes.
    Design: Twenty subjects (10 obese, 10 overweight) participated in a blinded, randomized, crossover study of dairy- compared with soy-supplemented eucaloric diets. Two 28-d dietary periods were separated by a 28-d washout period. Inflammatory and oxidative stress biomarkers were measured on days 0, 7, and 28 of each dietary period.
    Results: The dairy-supplemented diet resulted in significant suppression of oxidative stress (plasma malondialdehyde, 22%; 8-isoprostane-F2α, 12%; P < 0.0005) and lower inflammatory markers (tumor necrosis factor-α, 15%, P < 0.002; interleukin-6, 13%, P < 0.01; monocyte chemoattractant protein-1, 10%, P < 0.0006) and increased adiponectin (20%, P < 0.002), whereas the soy exerted no significant effect. These effects were evident by day 7 of treatment and increased in magnitude at the end of the 28-d treatment periods. There were no significant differences in response to treatment between overweight and obese subjects for any variable studied. Conclusion: An increase in dairy food intake produces significant and substantial suppression of the oxidative and inflammatory stress associated with overweight and obesity. This trial was registered at as NCT00686426.

    Am J Clin Nutr August 2011 vol. 94 no. 2 422-430
    Dairy attentuates oxidative and inflammatory stress in metabolic syndrome
    Renée A Stancliffe, Teresa Thorpe, and Michael B Zemel
    Background: Oxidative and inflammatory stress are elevated in obesity and are further augmented in metabolic syndrome. We showed previously that dairy components suppress the adipocyte- and macrophage-mediated generation of reactive oxygen species and inflammatory cytokines and systemic oxidative and inflammatory biomarkers in obesity.
    Objective: The objective of this study was to determine the early (7 d) and sustained (4 and 12 wk) effects of adequate-dairy (AD) compared with low-dairy (LD) diets in subjects with metabolic syndrome.
    Design: Forty overweight and obese adults with metabolic syndrome were randomly assigned to receive AD (3.5 daily servings) or LD (<0.5 daily servings) weight-maintenance diets for 12 wk. Oxidative and inflammatory biomarkers were assessed at 0, 1, 4, and 12 wk as primary outcomes; body weight and composition were measured at 0, 4, and 12 wk as secondary outcomes. Results: AD decreased malondialdehyde and oxidized LDL at 7 d (35% and 11%, respectively; P < 0.01), with further decreases by 12 wk. Inflammatory markers were suppressed with intake of AD, with decreases in tumor necrosis factor-α at 7 d and further reductions through 12 wk (35%; P < 0.05); decreases in interleukin-6 (21%; P < 0.02) and monocyte chemoattractant protein 1 (14% decrease at 4 wk, 24% decrease at 12 wk; P < 0.05); and a corresponding 55% increase in adiponectin at 12 wk (P < 0.01). LD exerted no effect on oxidative or inflammatory markers. Diet had no effect on body weight; however, AD significantly reduced waist circumference and trunk fat (P < 0.01 for both), and LD exerted no effect.
    Conclusion: An increase in dairy intake attenuates oxidative and inflammatory stress in metabolic syndrome. This trial was registered at as NCT01266330.

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    Leptin, Estrogen, Inflammation, Breast Cancer

    October 16th, 2014

    Also see:
    Sugar (Sucrose) Restrains the Stress Response
    Endotoxin: Poisoning from the Inside Out
    Ray Peat, PhD on Endotoxin
    Hormonal profiles in women with breast cancer
    Plasma Estrogen Does Not Reflect Tissue Concentration of Estrogen
    Pre and Postmenopausal Women: Progesterone Decreases Aromatase Activity
    Fat Tissue and Aging – Increased Estrogen
    Estrogen Related to Loss of Fat Free Mass with Aging
    How does estrogen enhance endotoxin toxicity? Let me count the ways.
    Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
    Breast Cancer by Ray Peat
    Preventing and treating cancer with progesterone by Ray Peat

    Quotes by Ray Peat, PhD:
    “I doubt that there is any biological significance in the idea of leptin resistance. Leptin promotes inflammation and cancer, so it might be good to be resistant to it, but I think the concept is mainly an outgrowth of the pharmaceutical industry’s promotion of leptin as a cure for obesity.”

    “Leptin (which is promoted by estrogen) is a hormone produced by fat cells, and it, like estrogen, activates the POMC-related endorphin stress system. The endorphins activate histamine, another promoter of inflammation and cell division.

    Progesterone opposes those various biochemical effects of estrogen in multiple ways, for example by inhibiting the ACTH stress response, by restraining cortisol’s harmful actions, and by inhibiting leptin.”

    Cell Immunol. 2008 Mar-Apr;252(1-2):139-45. doi: 10.1016/j.cellimm.2007.09.004. Epub 2008 Mar 4.
    Leptin beyond body weight regulation–current concepts concerning its role in immune function and inflammation.
    Lago R, Gómez R, Lago F, Gómez-Reino J, Gualillo O.
    Leptin, a 16 kDa non-glycosylated polypeptide produced primarily by adipocytes and released into the systemic circulation, exerts a multitude of regulatory functions including energy utilization and storage, regulation of various endocrine axes, bone metabolism, and thermoregulation. In addition to leptin’s best known role as regulator of energy homeostasis, several studies indicate that leptin plays a pivotal role in immune and inflammatory response. Because of its dual nature as a hormone and cytokine, leptin can be nowadays considered the link between neuroendocrine and immune system. The increase in leptin production that occurs during infections and inflammatory processes strongly suggests that this adipokine is a part of the cytokines network which governs inflammatory/immune response and host defence mechanisms. Indeed, leptin plays a relevant role in inflammatory processes involving either innate or adaptive immune responses. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as encephalomyelitis, type I diabetes, bowel inflammation and also articular degenerative diseases such as rheumatoid arthritis and osteoarthritis. Although the mechanisms by which leptin exerts its action as modulator of inflammatory/immune response are likely to be more complex than predicted and far to be completely depicted, there is a general consensus about its pivotal role as pro-inflammatory and immune-modulating agent. Here, we review the most recent advances on leptin biology with a particular attention to its adipokine facet, even though its role as metabolic hormone will be also addressed.

    Mol Cell Endocrinol. 2013 Apr 4. pii: S0303-7207(13)00121-4. doi: 10.1016/j.mce.2013.03.025. [Epub ahead of print]
    Leptin-cytokine crosstalk in breast cancer.
    Newman G, Gonzalez-Perez RR.
    Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman’s laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously decreased the levels of VEGF/VEGFR2, IL-1 and Notch. Inhibition of leptin-cytokine crosstalk might serve as a preventative or adjuvant measure to target breast cancer, particularly in obese women. This review is intended to present an update analysis of leptin actions in breast cancer, highlighting its crosstalk to inflammatory cytokines and growth factors essential for tumor development, angiogenesis and potential role in BCSC.

    Pathol Oncol Res. 2006;12(2):69-72. Epub 2006 Jun 24.
    Leptin–from regulation of fat metabolism to stimulation of breast cancer growth.
    Sulkowska M, Golaszewska J, Wincewicz A, Koda M, Baltaziak M, Sulkowski S.
    Leptin restricts intake of calories as a satiety hormone. It probably stimulates neoplastic proliferation in breast cancer, too. Growth of malignant cells could be regulated by various leptin-induced second messengers like STAT3 (signal transducers and activators of transcription 3), AP-1 (transcription activator protein 1), MAPK (mitogen-activated protein kinase) and ERKs (extracellular signal-regulated kinases). They seem to be involved in aromatase expression, generation of estrogens and activation of estrogen receptor alpha (ERalpha) in malignant breast epithelium. Leptin may maintain resistance to antiestrogen therapy. Namely, it increased activation of estrogen receptors, therefore, it was suspected to reduce or even overcome the inhibitory effect of tamoxifen on breast cell proliferation. Although several valuable reviews have been focused on the role of leptin in breast cancer, the status of knowledge in this field changes quickly and our insight should be continuously revised. In this summary, we provide refreshed interpretation of intensively reported scientific queries of the topic.

    J Cell Biochem. 2008 Nov 1;105(4):956-64. doi: 10.1002/jcb.21911.
    Leptin signaling in breast cancer: an overview.
    Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N.
    The adipocyte-derived peptide leptin acts through binding to specific membrane receptors, of which six isoforms (obRa-f) have been identified up to now. Binding of leptin to its receptor induces activation of different signaling pathways, including the JAK/STAT, MAPK, IRS1, and SOCS3 signaling pathways. Since the circulating levels of leptin are elevated in obese individuals, and excess body weight has been shown to increase breast cancer risk in postmenopausal women, several studies addressed the role of leptin in breast cancer. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma. Leptin is able to induce the growth of breast cancer cells through activation of the Jak/STAT3, ERK1/2, and/or PI3K pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF). In addition, leptin induces transactivation of ErbB-2, and interacts in triple negative breast cancer cells with insulin like growth factor-1 (IGF-1) to transactivate the epidermal growth factor receptor (EGFR), thus promoting invasion and migration. Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK-dependent activation of ER. Taken together, these findings suggest that the leptin system might play an important role in breast cancer pathogenesis and progression, and that it might represent a novel target for therapeutic intervention in breast cancer.

    Mini Rev Med Chem. 2006 Aug;6(8):897-907.
    Leptin, estrogens and cancer.
    Maeso Fortuny MC, Brito Díaz B, Cabrera de León A.
    Obesity is a state of leptin resistance in which the membrane leptin receptor and the JAK-STAT pathway are blocked. This leads to increased intracellular concentrations of lipid metabolites, increased non-oxidative metabolism by adipocytes, and stimulation of the cell estrogen cycle. These factors are potentially oncogenic via the shared mitogen-activated protein kinase (MAPK), mitogen/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK) cellular pathways.

    Expert Opin Investig Drugs. 2005 Mar;14(3):251-64.
    Parathyroid hormone and leptin–new peptides, expanding clinical prospects.
    Whitfield JF.
    Leptin, a member of the cytokine superfamily has a PTH-like osteogenic activity and may even partly mediate PTH action. But leptin has two drawbacks that cloud its therapeutic future. First, apart from directly stimulating osteoblastic cells, it targets cells in the hypothalamic ventromedial nuclei and through them it reduces oestrogenic activity by promoting osteoblast-suppressing adrenergic activity. Second, it stimulates vascular and heart valve ossification, which leads to such events as heart failure and diabetic limb amputations.

    Endocrinology 2001 Jul;142(7):2796-804.
    Sucrose ingestion normalizes central expression of corticotropin-releasing-factor messenger ribonucleic acid and energy balance in adrenalectomized rats: a glucocorticoid-metabolic-brain axis?
    Laugero KD, Bell ME, Bhatnagar S, Soriano L, Dallman MF.
    Both CRF and norepinephrine (NE) inhibit food intake and stimulate ACTH secretion and sympathetic outflow. CRF also increases anxiety; NE increases attention and cortical arousal. Adrenalectomy (ADX) changes CRF and NE activity in brain, increases ACTH secretion and sympathetic outflow and reduces food intake and weight gain; all of these effects are corrected by administration of adrenal steroids. Unexpectedly, we recently found that ADX rats drinking sucrose, but not saccharin, also have normal caloric intake, metabolism, and ACTH. Here, we show that ADX (but not sham-ADX) rats prefer to consume significantly more sucrose than saccharin. Voluntary ingestion of sucrose restores CRF and dopamine-beta-hydroxylase messenger RNA expression in brain, food intake, and caloric efficiency and fat deposition, circulating triglyceride, leptin, and insulin to normal. Our results suggest that the brains of ADX rats, cued by sucrose energy (but not by nonnutritive saccharin) maintain normal activity in systems that regulate neuroendocrine (hypothalamic-pituitary-adrenal), behavioral (feeding), and metabolic functions (fat deposition). We conclude that because sucrose ingestion, like glucocorticoid replacement, normalizes energetic and neuromodulatory effects of ADX, many of the actions of the steroids on the central nervous system under basal conditions may be indirect and mediated by signals that result from the metabolic effects of adrenal steroids.

    Ginekol Pol. 1999 Jan;70(1):1-7.
    Leptin regulation of aromatase activity in adipose stromal cells from regularly cycling women.
    Magoffin DA, Weitsman SR, Aagarwal SK, Jakimiuk AJ.
    Leptin, a product of adipocytes, is a cytokine with multiple effects on the reproductive axis. Leptin causes the activation of STAT proteins within target cells. The aromatase gene promoter in adipose stromal cells contains a functional STAT binding region, leading to the hypothesis that leptin may regulate aromatase activity in fat tissue. To test this hypothesis, adipose stromal cells were isolated from subcutaneous abdominal fat or breast fat then placed into tissue culture.
    The cells were treated for three days with increasing concentrations of recombinant human leptin. Aromatase activity in the stromal cells was measured by the release of 3H2O from radiolabeled androstenedione precursor.
    Basal aromatase activity varied markedly between, but there were no differences between abdominal fat and breast fat. Leptin concentrations in the physiological range of normal weight or thin women (10 ng/ml) had no effect on aromatase activity. In 2 of 8 abdominal fat cultures and 1 of 2 breast fat cultures, a high obese concentration of leptin (100 ng/ml) stimulated a significant increase in aromatase activity. In the remaining subjects there was no effect of leptin, even at high concentrations.
    These data demonstrate that in approximately 30 percent of our subject population leptin was able to stimulate aromatase activity in adipose stromal cells at high concentrations. The elevated levels of aromatase activity may contribute to increase circulating estrogen levels in certain obese women and suggest that elevated leptin concentrations in obese women may cause locally elevated estrogen concentrations in the breast and thereby promote tumor formation.

    Contrib Nephrol. 2006;151:151-64.
    Leptin as a proinflammatory cytokine.
    Lord GM.
    Leptin is a 16-kDa protein produced mainly by adipocytes. Animal models demonstrate that leptin is required for control of bodyweight and reproduction, since mice defective in leptin or the leptin receptor are obese, hyperphagic insulin resistant and infertile. Our initial series of observations lead us to propose that leptin also had significant effects on human type I proinflammatory immune responses. In support of this hypothesis, leptin deficient mice are resistant to a wide range of autoimmune diseases and display features of immune deficiency. Subsequent work has confirmed that leptin has a pleiotrophic role on the immune response and can rightly be considered, both structurally and functionally, as a proinflammatory cytokine.

    Fertil Steril. 2010 Aug;94(3):1037-43.
    Serum leptin levels, hormone levels, and hot flashes in midlife women.
    Alexander C, Cochran CJ, Gallicchio L, Miller SR, Flaws JA, Zacur H.
    To examine the associations between serum leptin levels, sex steroid hormone levels, and hot flashes in normal weight and obese midlife women.
    Cross-sectional study.
    University clinic.
    201 Caucasian, nonsmoking women aged 45 to 54 years with a body mass index of <25 kg/m2 or >or=30 kg/m2.
    Questionnaire, fasting blood samples.
    Serum leptin and sex steroid hormone levels.
    Correlation and regression models were performed to examine associations between leptin levels, hormone levels, and hot flashes. Leptin levels were associated with BMI, with “ever experiencing hot flashes” (questionnaire), with hot flashes within the last 30 days, and with duration of hot flashes (>1 year, P=.03). Leptin was positively correlated with testosterone, free testosterone index, and free estrogen index and inversely associated with levels of sex hormone-binding globulin. In women with a body mass index>or=30 kg/m2, leptin levels no longer correlated with testosterone levels.
    Serum leptin levels are associated with the occurrence and duration of hot flashes in midlife women; however, no correlation was found between leptin and serum estradiol.

    Endocr Relat Cancer. 2010 Apr 21;17(2):373-82.
    Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting.
    Fusco R, Galgani M, Procaccini C, Franco R, Pirozzi G, Fucci L, Laccetti P,
    Matarese G.
    Obesity is associated with an increased risk of breast cancer. A number of adipocytokines are increased in obesity causing low-level chronic inflammation associated with an increased risk of tumors. The adipocytokine leptin shows profound anti-obesity and pro-inflammatory activities. We have hypothesized that in common obesity, high circulating leptin levels might contribute to an increased risk of breast cancer by affecting mammary cell proliferation and survival. Leptin exerts its activity not only through leptin receptor (LepR), but also through crosstalk with other signaling systems implicated in tumorigenesis. In this study, we focused our attention on the relationship between the leptin/LepR axis and the estrogen receptor-alpha (ERalpha). To this aim, we utilized two human breast cancer cell lines, one ERalpha-positive cell line (MCF 7) and the other ERalpha-negative cell line (MDA-MB 231). We observed that the two cell lines had a different sensitivity to recombinant leptin (rleptin): on MCF 7 cells, rleptin induced a strong phosphorylation of the signal transducer and activator of transcription (STAT) 3 and of the extracellular related kinase 1/2 pathways with an increased cell viability and proliferation associated with an increased expression of ERalpha receptor. This response was not present in the MDA-MB 231 cells. The effects induced by leptin were lost when LepR was neutralized using either a monoclonal inhibitory antibody to LepR or LepR gene-silencing siRNA. These data suggest that there is a bidirectional communication between LepR and ERalpha, and that neutralization and/or inactivation of LepR inhibits proliferation and viability of human breast cancer cell lines. This evidence was confirmed by ex vivo studies, in which we analyzed 33 patients with breast cancer at different stages of disease, and observed that there was a statistically significant correlation between the expression of LepR and ERalpha. In conclusion, this study suggests a crosstalk between LepR and ERalpha, and could envisage novel therapeutic settings aimed at targeting the LepR in breast cancers.

    J Clin Endocrinol Metab. 2003 Mar;88(3):1285-91.
    Endotoxin stimulates leptin in the human and nonhuman primate.
    Landman RE, Puder JJ, Xiao E, Freda PU, Ferin M, Wardlaw SL.
    Leptin, which plays a key role in regulating energy homeostasis, may also modulate the inflammatory response. An inflammatory challenge with endotoxin has been shown to stimulate leptin release in the rodent. This finding has not been reproduced in humans or in nonhuman primates, although leptin levels have been reported to increase in septic patients. We have therefore examined the effects of endotoxin injection on plasma leptin levels in nine ovariectomized monkeys and four postmenopausal women. In an initial study in five monkeys, mean leptin levels did not increase during the first 5 h after endotoxin treatment, but did increase significantly from 6.4 +/- 2.1 ng/ml at baseline to 12.3 +/- 4.4 ng/ml at 24 h (P = 0.043). In a second study, a significant increase in leptin over time was noted after endotoxin treatment (P < 0.001); leptin release during the 16- to 24-h period after endotoxin injection was 48% higher than during the control period (P = 0.043). A similar stimulatory effect of endotoxin on leptin was observed when monkeys received estradiol replacement. In a third study, repeated injections of endotoxin over a 3-d period stimulated IL-6, ACTH, cortisol, and leptin release (P < 0.001). Leptin increased during the first day of treatment in all animals, but only monkeys with baseline plasma leptin levels greater than 10 ng/ml exhibited a sustained increase in leptin throughout the 3-d period. There was a significant correlation (r = 0.81; P = 0.008) between the mean baseline leptin level and the percent increase in leptin over baseline on the last day of treatment. In the human subjects, plasma leptin concentrations did not change significantly during the 7-h period after endotoxin injection. However, leptin increased in all four women from a mean baseline of 8.34 +/- 3.1 to 13.1 +/- 4.3 ng/ml 24 h after endotoxin (P = 0.038). In summary, endotoxin stimulates the release of leptin into peripheral blood in the human and nonhuman primate, but the time course is different from that reported in the rodent. These results are consistent with previous reports of increased blood leptin levels in patients with sepsis. The significance of these findings and the potential role of leptin in modulating the response to inflammation in the human require further study.

    J Leukoc Biol. 2000 Oct;68(4):437-46.
    Leptin in the regulation of immunity, inflammation, and hematopoiesis.
    Fantuzzi G, Faggioni R.
    Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and antiapoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis.

    Exp Clin Endocrinol Diabetes. 1999;107(2):119-25.
    Mechanisms of TNF-alpha-induced insulin resistance.
    Hotamisligil GS.
    There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha’s promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.

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    Common Paths to a High Metabolism

    August 5th, 2014

    Also see:
    Common Paths to a Low Metabolism
    Promoters of Efficient v. Inefficient Metabolism
    Collection of FPS Charts
    Collection of Ray Peat Quote Blogs by FPS
    Master List – Ray Peat, PhD Interviews
    Components of Daily Energy Expenditure
    Body Temperature, Metabolism, and Obesity

    This chart provides several ways in which cell metabolism is optimized by nutrition and lifestyle factors. Multiple factors should be acting together. Juxtapose the chart in this blog with the Common Paths to a Low Metabolism chart.

    Commonalities among the factors in the “Common Paths to a High Metabolism” chart are consistency in effort and preparation, lean tissue preservation or gain, focus on cellular needs, thyroid system support, blood sugar regulation, a diet rooted in historically relevant and digestible foodstuffs, emphasis on light exposure, recognition of the importance of regenerative sleep and a consistent sleep cycle, conscious avoidance of anti-metabolic factors, steroid hormone balance, and stress reduction.

    FPS High Metabolism


    Universal Principle of Cellular Energy

    June 21st, 2014

    Also see:
    Mitochondrial Medicine
    Protect the Mitochondria
    Collection of Ray Peat Quote Blogs by FPS
    Carbon Dioxide as an Antioxidant
    Carbon Dioxide Basics
    Comparison: Carbon Dioxide v. Lactic Acid
    Comparison: Oxidative Metabolism v. Glycolytic Metabolic
    Promoters of Efficient v. Inefficient Metabolism
    ATP Regulates Cell Water
    Cardiolipin, Cytochrome Oxidase, Metabolism, & Aging
    High Cholesterol and Metabolism
    Low CO2 in Hypothyroidism
    Protective Altitude
    Lactate Paradox: High Altitude and Exercise
    Protective Carbon Dioxide, Exercise, and Performance
    Mitochondrial medicine
    Low Carb Diet – Death to Metabolism
    Low Blood Sugar Basics
    The Cholesterol and Thyroid Connection
    Thyroid Status and Oxidized LDL
    Hypothyroidism and A Shift in Death Patterns
    Light is Right
    Using Sunlight to Sustain Life
    PUFA Decrease Cellular Energy Production
    PUFA Breakdown Products Depress Mitochondrial Respiration
    “Curing” a High Metabolic Rate with Unsaturated Fats
    Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
    Altitude Improves T3 Levels
    Mitochondria & Mortality
    Altitude and Mortality
    Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer
    Power Failure: Does mitochondrial dysfunction lie at the heart of common, complex diseases like cancer and autism?
    Faulty Energy Production in Brain Cells Leads to Disorders Ranging from Parkinson’s to Intellectual Disability
    Energy, structure, and carbon dioxide: A realistic view of the organism
    Metabolic features of the cell danger response

    When someone who has not been exposed to Ray Peat’s work, he/she can react with surprise when he/she hears that sugar, aspirin, milk/calcium, red light, salt, coffee, and saturated fats (to name a few) are recommended. This blog provides the foundational context required to begin to meaningfully interpret the 40+ years of writing from Dr. Peat.

    The reason why the aforementioned therapies are important in a “Peatarian” lifestyle comes down to what I’m calling the Universal Principle of Cellular Energy but call the idea whatever you wish. The principle is universal in this way — it applies to all chronic health problems regardless of what medicine calls it. The thumbnail below attempts to provide the highlights of the concept.

    UPCE fps

    The substrate that cells need to make energy comes from the foods we eat; glucose oxidation produces the most ATP and carbon dioxide relative to other substrates and is synonymous with youthfulness and good health. This is why the dietary sugar component becomes important and carbohydrate avoidance is illogical.

    Cellular energy deficiency leads to decreased renewal and the rate of aging speeds up progressively as adaptation becomes increasingly imperfect as cells become exhausted. If the energy crisis is severe, it can lead to cell death. Aging and disease(s) are representations of the body’s unique series of adaptations to an energy problem. The needs of your cells guide what actions your physiology takes to survive. Your cells can only do what the environment allows so it’s up to us to provide the optimal environment for energy success.

    The principle can serve as the base by which nutritional decisions or therapies can be implemented. It’s also helpful in recognizing where someone may have done harm in his/her past. If you’re in a health rut, start by recognizing factors that slow down energy production and learn how to oppose these factors with pro-energy foods, lifestyle change, and supplements. Chief among the anti-energy factors are estrogen, polyunsaturated fats, endotoxin, serotonin, nitric oxide, darkness, and radiation. Thanks to inspiration by Dr. Peat, the FPS blog provides information on all of these factors.

    Supportive Quotes by Ray Peat, PhD:
    “If we learn to see problems in terms of a general disorder of energy metabolism, we can begin to solve them.”

    “A given structure makes possible a certain level of useful energy, and adequate energy makes possible the maintenance of structure, and the advance to a higher and more efficient structural level.”

    “I started my work with progesterone and related hormones in 1968. In papers in Physiological Chemistry and Physics (1971 and 1972) and in my dissertation (University of Oregon, 1972), I outlined my ideas regarding progesterone, and the hormones closely related to it, as protectors of the body’s structure and energy against the harmful effects of estrogen, radiation, stress, and lack of oxygen.

    The key idea was that energy and structure are interdependent, at every level.

    Since then, I have been working on both practical and theoretical aspects of this view. I think only a new perspective on the nature of living matter will make it possible to properly take advantage of the multitude of practical and therapeutic effects of the various life-supporting substances–pregnenolone, progesterone, thyroid hormone, and coconut oil in particular.”

    “Life interposes itself between the “poles” of energy flow, and the flowing energy creates organization and structure, as it is dissipated into heat. Structures store some of the energy, and tend to increase in complexity, taking advantage of the flow of energy to create phase differences with expanded internal surfaces, like a finely mixed emulsion. Like a finely divided emulsion, the more highly energized the organism is, the stabler it is.”

    “It seems that all of the problems of development and degeneration can be alleviated by the appropriate use of the energy-protective materials. When we realize that our human nature is problematic, we can begin to explore our best potentials.”

    “A high level of respiratory energy production that characterizes young life is needed for tissue renewal. The accumulation of factors that impair mitochondrial respiration leads to increasing production of stress factors, that are needed for survival when the organism isn’t able to simply produce energetic new tissue as needed. Continually resorting to these substances progressively reshapes the organism, but the investment in short-term survival, without eliminating the problematic factors, tends to exacerbate the basic energy problem.”

    “The biological idea of stress refers to the difficulty of adapting, and this involves energy, structure, and insight/orientation. Given enough energy, we can often adjust our structure to achieve full adaptation, and with insight, we can minimize the amount of energy and structural change needed, for example just by a change of pace or rhythm.”

    “The metabolic interpretation of disease that had been making progress for several decades was suddenly submerged when government research financing began concentrating on genetic and viral interpretations of disease.”

    “The availability of energy is central to our stable functioning, and the need for energy powerfully modifies our functioning.”

    “Stress is an energy problem, that leads to the series of hormonal and metabolic reactions –lipolysis, glycolysis, increased serotonin, cortisol, estrogen, prolactin, leaky capillaries, protein catabolism, etc.”

    “There is a repolarization of the cell after the production of ATP and CO2; the cell then gets ready to make more energy. Essentially the cell should be in a relaxed state as it gathers all of its forces to make energy. It then makes energy and goes back into its readiness state.”

    “The intensity of oxidative metabolism is the basic factor that permits continuing coordination of activity, and harmonious renewal of all the components of the organism.”

    “If we optimize the known factors which improve energy production (red light, short-chain and medium-chain saturated fats, and pregnenolone, for example), to the extent that our metabolism resembles that of a ten year old child, I don’t think there is any reason to suppose that we wouldn’t have regenerative, healing abilities which are common at that age.”

    “In every type of tissue, it is the failure to oxidize glucose that produces oxidative stress and cellular damage.”

    “Energy metabolism is the central biochemical issue.”

    “Energy generates order and maintains it. Destruction of order degrades the ability of cells to produce energy.”

    “Metabolic energy is fundamental to the development and maintenance of the body, and to the “ways in which living beings react to changed circumstances.” It’s an obvious first thing to consider when thinking about any “disease,” whether it’s cancer, radiation, sickness, dementia, depression, or traumatic injury.”

    “The regulation of cell renewal probably involves all of the processes of life, but there are a few simple, interacting factors that suppress renewal. The accumulation of polyunsaturated fats, interacting with a high concentration of oxygen, damages mitochondria, and causes a chronic excessive exposure to cortisol. With mitochondrial damage, cells are unable to produce the progesterone needed to oppose cortisol and to protect cells.

    Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic engineers. “

    “Aging is an energy problem, and in the brain, which has extremely high energy requirements, interference with the energy supply quickly causes cells to die.”

    “The balance between what a tissue needs and what it gets will govern the way that tissue functions, in both the short term and the long term. When a cell emits lactic acid and free radicals and the products of lipid peroxidation, it’s reasonable to assume that it isn’t getting everything that it needs, such as oxygen and glucose. With time, the cell will either die or adapt in some way to its deprived conditions.”

    “The needs on the cellular level guide the organism’s adaptation.”

    “Many of the anti-adaptive features of old blood can be reduced. Long daylight hours and high altitude (the altitude “lactate paradox” is an example of a cellular oxidative increase caused by lower oxygen pressure) shift the balance of some of the factors, and others can be improved by modifying the diet, and supplementing with things such as the protective steroids, thyroid hormone, aspirin, niacinamide (which can increase the oxidized state of NADH/NAD+), and caffeine. Providing the things needed for cellular energy while blocking some of the maladaptive factors approaches the problem of aging in a fundamental and holistic way.”

    “In the excessively sensitive condition produced by hypoglycemia, several things happen that contribute to the maladaptive exaggerated inflammatory response. Adrenaline increases in hypoglycemia, and, if the adrenaline fails to convert glycogen into glucose, it will provide an alternative fuel by liberating free fatty acids from fat cells. If the liberated fatty acids are unsaturated, they will cause serotonin to be secreted, and both serotonin and the unsaturated fatty acids will suppress mitochondrial respiration, exacerbating the hypoglycemia. They will stimulate the release of cytokines, activating a variety of immunological and inflammatory processes, and they will cause blood vessels to become leaky, creating edema and starting the first stages of fibrosis. Both adrenaline and serotonin will stimulate the release of cortisol, which mobilizes amino acids from tissues such as the large skeletal muscles. Those muscles contain a large amount of cysteine and tryptophan, which, among other effects, suppress the thyroid. The increased tryptophan, especially in the presence of free fatty acids, is likely to be converted into additional serotonin, since fatty acids release tryptophan from albumin, increasing its entry into the brain. Free fatty acids and increased serotonin reduce metabolic efficiency (leading to insulin resistance, for example) and promote an inflammatory state.”

    “When the available energy doesn’t meet the cell’s energy requirements, if the cell isn’t quickly killed by stress, it will use some adaptive mechanisms, stopping some repair processes to reduce energy expenditure, possibly stopping specialized functions to reduce energy needs. Fibrotic changes occur as a result of defensive reactions in stressed cells, usually following long periods of fatigue and inflammation.”

    “When cells are in an energy deficient state, as in hypothyroidism, they are in the leaky edematous state.”

    “Szent-Gyorgyi observed that, although ATP was involved in the contractions of muscles, its post-mortem disappearance caused the contraction and hardening of muscle known as rigor mortis. When he put hardened dead muscles into a solution of ATP, they relaxed and softened. The relaxed state is a state with adequate energy reserves.”

    “Cells in their excited and exhausted state are increasingly open to penetration of toxins because of their own increased permeability and because of the increased leakiness of the blood vessels. Certain environmental toxins accumulate more rapidly as the cells lose their ability to destroy them. Several kinds of toxins, including unsaturated fats, inhibit the proteolytic enzymes that remodel tissue, and reduce the ability to dismantle and rebuild the cellular matrix.”

    “Sugar can be used to produce energy with or without oxygen, but oxidative metabolism is about 15 times more efficient than the non-oxidative “glycolytic” or fermentive metabolism; higher organisms depend on this high efficiency oxidation for maintaining integration and normal functioning: If there is a small interference with respiration, the organism can adapt by increasing the rate of glycolysis, but there must be enough sugar to meet the demand. A response to stimulation is the production of more energy, with a proportional increase of oxygen and sugar consumption by the stimulated tissue; this produces more carbon dioxide. which enlarges the blood vessels in the area, providing more sugar and oxygen. If the irritation becomes destructive, efficiency is lost: oxygen is either consumed wastefully, causing blueness of the tissue (assuming circulation continues: blueness can also indicate bad circulation), or is not consumed. causing redness of the tissue. As more sugar is consumed in compensation, lactic acid also enlarges the blood vessels.

    If the inflamed or exhausted tissue is small, the lactic acid can be consumed by other oxidizing tissues, sufficient sugar usually can be supplied, and repair occurs. But a large inflammation. or profound exhaustion, will lower the blood sugar systemically, and will deliver large amounts of lactic acid to the liver. The liver synthesizes glucose from the lactic acid, but at the expense of about 6 times more energy than is obtained from the inefficient metabolism – so that organismically, that tissue becomes 90 times less efficient than its original state. Besides this, an idle destruction of energy molecules (ATP or creatine phosphate) will increase the wastefulness even more.”

    “The loss of control over water in the body is a result of energy failure…”

    “As in other cells, ATP maintains the proper water content of cells.”

    “…the essential element of stress is the inadequacy of energy to meet a challenge, and when energy is inefficient water is taken up.”

    “When respiration is blocked tissues take up water.”

    “Stress increases metabolic rate in a destructive, age accelerating way, with increased inflammation, and decreased resting oxidative metabolic rate. It’s the basic metabolic rate, with fast nerve conduction, quick cellular adaptation, etc., that’s biologically valuable.”

    “The result of these passive and active processes is that each kind of ion has a characteristic concentration in each compartment, according to the metabolic energy state of the organism. 

    Magnesium and potassium are mainly intracellular ions, sodium and calcium are mainly extracellular ions. When cells are excited, stressed, or de-energized, they lose magnesium and potassium, and take up sodium and calcium. The mitochondria can bind a certain amount of calcium during stress, but accumulating calcium can reach a point at which it inactivates the mitochondria, forcing cells to increase their inefficient glycolytic energy production, producing an excess of lactic acid. Abnormal calcification begins in the mitochondria. 

    When cells are stressed or dying, they take up calcium, which tends to excite the cells at the same time that it inhibits their energy production, intensifying their stress. A cramp or a seizure is an example of uncontrolled cellular excitation. Prolonged excitation and stress contribute to tissue inflammation and fibrosis.

    Gross calcification generally follows the fibrosis that is produced by inflammation.

    Arteries, kidneys, and other organs calcify during aging. At the age of 90, the amount of calcium in the elastic layer of an artery is about 35 times greater than at the age of 20. Nearly every type of tissue, including the brain, is susceptible to the inflammatory process that leads through fibrosis to calcification. The exception is the skeleton, which loses its calcium as the soft tissues absorb calcium.

    These observations lead to some simplifying ideas about the nature of aging and disease.

    Some people who know about the involvement of calcium in aging, stress, and degeneration suggest eating a low calcium diet, but since we all have skeletons, dietary calcium restriction cant protect our cells, and in fact, it usually intensifies the process of calcification of the soft tissues. Statistics from several countries have clearly shown that the mortality rate (especially from arteriosclerotic heart disease, but also from some other diseases, including cancer) is lower than average in regions that have hard water, which often contains a very large amount of either calcium or magnesium.”

    “Much of the intracellular magnesium is complexed with ATP, and helps to stabilize that molecule. If cellular energy production is low, as in hypothyroidism, cells tend to lose their magnesium very easily, shifting the balance toward the lower energy molecule, ADP, with the release of phosphate. ADP complexes with calcium, rather than magnesium, increasing the cells calcium content.”

    “Degenerative diseases, especially cancer, heart disease, and brain diseases, are less prevalent in populations that live at a high altitude. When oxygen pressure is low, the lungs lose carbon dioxide more slowly, and so the amount of carbon dioxide retained in the body is greater. If the basic problem in hypothyroidism is the deficient production of carbon dioxide causing excessive loss of salt and retention of water, resulting in hypo-osmotic body fluids, then we would expect people at high altitude to have better retention of salt, more loss of water, and more hypertonic body fluids.”

    “Since respiratory metabolism, governed by the thyroid hormone, is our main source of carbon dioxide, it’s obvious that thyroid deficiency should impair our ability to regulate water and solutes, such as salt.”

    “The degenerative diseases can be seen as the cumulative result of stress, in which tissue damage results from the diabetes-like impairment of energy production.”

    “Any stress or energy deficit that disturbs cellular structure or function disturbs the interactions among water, proteins, and other components of the cell. Excitation causes a cell to take up extra water, not by osmosis resulting from an increase in the concentration of solutes in the cell, or because the membrane has become porous, but because the structural proteins of the cell have momentarily increased their affinity for water.

    This increased affinity is similar to the process that causes a gel to swell in the presence of alkalinity, and it is related to the process called electroosmosis, in which water moves toward a higher negative charge. Intense excitation or stress increases the cell’s electrically negative charges, and causes it to become more alkaline and to swell. Swelling and alkalinity cause the cell to begin the synthesis of DNA, in preparation for cell division.”

    “The higher rate of metabolism produced by adequate thyroid function maintains a high rate of renewal of the cell’s systems, keeping the cell constantly adjusted to slight changes in the organism’s needs.”

    “In hypothyroidism and diabetes, respiration is impaired, and lactic acid is formed even at rest, and relatively little carbon dioxide is produced. To compensate for the metabolic inefficiency of hypothyroidism, adrenalin and noradrenalin are secreted in very large amounts. Adrenalin causes free fatty acids to circulate at much higher levels, and the lactic acid, adrenalin, and free fatty acids all stimulate hyperventilation. The already deficient carbon dioxide is reduced even more, producing respiratory alkalosis. Free fatty acids, especially unsaturated fats, increase permeability of blood vessels, allowing proteins and fats to enter the endothelium and smooth muscle cells of the blood vessels. Lactic acid itself promotes an inflammatory state, and in combination with reduced CO2 and respiratory alkalosis, contributes to the hyponatremia (sodium deficiency) that is characteristic of hypothyroidism. This sodium deficiency and osmotic dilution causes cells to take up water, increasing their volume.”

    “Thyroid, which opposes estrogen’s effects on cell energy, stimulates oxidative metabolism with the production of carbon dioxide, and reduces the water content of tissues.”

    “Estrogen seems to work by blocking oxidative metabolism, and its first visible effect is to cause the stimulated tissue to take up water. Anything that causes cells to take up water seems to stimulate cell division.”

    “This is where the issue of cell water comes in. Carbon dioxide, produced by oxidative cell metabolism, is associated with the high energy state of the cell. When something interferes with oxidative metabolism, lactic acid is produced instead of carbon dioxide. If the cell stays very long in this low oxygen state, it swells, taking up water. (The fatigued muscle, for example, can take up so much water in a short time that it weighs 20% more than before it began working so intensely that its energy needs far exceeded the availability of oxygen. This swelling is what causes the soreness and tightness of intense exercise. The swelling persists long after the liver has cleared the lactic acid from the blood.) This swelling from taking up water is involved in one type of “edema,” and in inflammation, or activation of the cells by hormones, as well as by simple oxygen deprivation.”

    “Lactate formation from glucose is increased when anything interferes with respiratory energy production, but lactate, through a variety of mechanisms, can itself suppress cellular respiration. (This has been called the Crabtree effect.) Lactate can also inhibit its own formation, slowing glycolysis. In the healthy cell, the mitochondrion keeps glycolysis working by consuming pyruvate and electrons (or “hydrogens”) from NADH, keeping the cell highly oxidized, with a ratio of NAD+/NADH of about 200. When the mitochondrion’s ability to consume pyruvate and NADH is limited, the pyruvate itself accepts the hydrogen from NADH, forming lactic acid and NAD+ in the process. As long as lactate leaves the cell as fast as it forms, glycolysis will provide ATP to allow the cell to survive. Oxygen and pyruvate are normally “electron sinks,” regenerating the NAD+ needed to produce energy from glucose.

    But if too much lactate is present, slowing glycolytic production of ATP, the cell with defective respiration will die unless an alternative electron sink is available. The synthesis of fatty acids is such a sink, if electrons (hydrogens) can be transferred from NADH to NADP+, forming NADPH, which is the reducing substance required for turning carbohydrates and pyruvate and amino acids into fats.”

    “While Warburg was investigating the roles of glycolysis and respiration in cancer, a physician with a background in chemistry, W.F. Koch, in Detroit, was showing that the ability to use oxygen made the difference between health and sickness, and that the cancer metabolism could be corrected by restoring the efficient use of oxygen. He argued that a respiratory defect was responsible for immunodeficiency, allergy, and defective function of muscles, nerves, and secretory cells, as well as cancer. Koch’s idea of cancer’s metabolic cause and its curability directly challenged the doctrine of the genetic irreversibility of cancer that was central to governmental and commercial medical commitments.”

    “A focus on correcting the respiratory defect would be relevant for all of the diseases and conditions (including heart disease, diabetes, dementia) involving inflammation and inappropriate excitation, not just for cancer.”

    “Aging is characterized by loss of lean body mass, immunodeficiency, and a variety of autoimmune reactions. My perennial argument has been that decreased thyroid and progesterone, associated with increased estrogen and stress hormones, are largely responsible for those changes.”

    “When respiratory energy production is blocked in stimulated cells, the cells are likely to die. (Cortisol, estrogen, polyunsaturated oils have this effect, especially on thymus cells.)”

    “Thyroid is needed to keep the cell in an oxidative, rather than reductive state, and progesterone (which is produced elsewhere only when cells are in a rapidly oxidizing state) activates the processes that remove estrogen from the cell, and inactivates the processes that would form new estrogen in the cell.

    Thyroid, and the carbon dioxide it produces, prevent the formation of the toxic lactic acid. When there is enough carbon dioxide in the tissues, the cell is kept in an oxidative state, and the formation of toxic free radicals is suppressed. Carbon dioxide therapy is extremely safe.”

    “The organism can only be understood in its environments, and a cell can’t be understood without reference to the tissue and organism in which it lives. Although the geneticists were at first hostile to the idea that nutrition and geography could have anything to do with cancer, they soon tried to dominate those fields, insisting that mutagens and ethnicity would explain everything. But the evidence now makes it very clear that environment and nutrition affect the risk of cancer in ways that are not primarily genetic.”

    “Substances such as PTH, nitric oxide, serotonin, cortisol, aldosterone, estrogen, thyroid stimulating hormone, and prolactin have regulatory and adaptive functions that are essential, but that ideally should act only intermittently, producing changes that are needed momentarily. When the environment is too stressful, or when nutrition isn’t adequate, the organism may be unable to mobilize the opposing and complementary substances to stop their actions. In those situations, it can be therapeutic to use some of the nutrients as supplements.”

    “The movement of substances from blood to cell, and from cell to cell, is normally very tightly controlled, and when the systems that control those movements of water and its solutes are damaged, the tissues’ structures and functions are altered. The prevention of inappropriate leakiness can protect against the degenerative processes, and against aging itself, which is, among other things, a state of generalized leakiness.

    When cells’ energy is depleted, water and various dissolved molecules are allowed to move into the cells, out of the cells, and through or around cells inappropriately. The weakened cells can even permit whole bacteria and similar particles to pass into and out of the blood stream more easily.

    One of the earliest investigators of the effects of stress and fatigue on nerves and other cells was A.P. Nasonov, in the first half of the 20th century. A.S. Troshin (1956) has reviewed his work in detail. He showed that in cells as different as algae and nerve cells, fatigue caused them to take up dyes, and that the dyes were extruded, if the cells were able to recover their energy. When nerve cells are excited for a fraction of a second, they take up sodium and calcium, but quickly eliminate them. Prolonged excitation, leading to fatigue, can gradually shift the balance, allowing more substances to enter, and to stay longer.”

    “If the cancer-productive field is taken into account, all of the factors that promote and sustain that field should be considered during therapy.

    Two ubiquitous carcinogenic factors that can be manipulated without toxins are the polyunsaturated fatty acids (PUFA) and estrogen. These closely interact with each other, and there are many ways in which they can be modulated.

    For example, keeping cells in a well oxygenated state with thyroid hormone and carbon dioxide will shift the balance from estradiol toward the weaker estrone. The thyroid stimulation will cause the liver to excrete estrogen more quickly, and will help to prevent the formation of aromatase in the tissues. Low temperature is one of the factors that increases the formation of estrogen. Lactic acid, serotonin, nitric oxide, prostaglandins, and the endorphins will be decreased by the shift toward efficient oxidative metabolism.

    Progesterone synthesis will be increased by the higher metabolic rate, and will tend to keep the temperature higher.

    Thyroid hormone, by causing a shift away from estrogen and serotonin, lowers prolactin, which is involved in the promotion of several kinds of cancer.

    Vitamin D and vitamin K have some antiestrogenic effects. Vitamin D and calcium lower the inflammation-promoting parathyroid hormone (PTH).

    Eliminating polyunsaturated fats from the diet is essential if the bystander effect is eventually to be restrained. Aspirin and salicylic acid can block many of the carcinogenic effects of the PUFA. Saturated fats have a variety of antiinflammatory and anticancer actions. Some of those effects are direct, others are the result of blocking the toxic effects of the PUFA. Keeping the stored unsaturated fats from circulating in the blood is helpful, since it takes years to eliminate them from the tissues after the diet has changed. Niacinamide inhibits lipolysis. Avoiding over-production of lipolytic adrenaline requires adequate thyroid hormone, and the adjustment of the diet to minimize fluctuations of blood sugar.”

    “Failure to renew cells and tissues leads to loss of function and substance. Bones and muscles get weaker and smaller with aging. Diminished bone substance, osteopenia, is paralleled, at roughly the same rate, by the progressive loss of muscle mass, sarcopenia (or myopenia). The structure of aging tissue changes, with collagen tending to fill the spaces left by the disappearing cells. It’s also common for fat cells to increase, as muscle cells disappear.”

    “Excitotoxicity, in its simplest sense, is the harmful cellular effect (death or injury) caused by an excitatory transmitter such as glutamate or aspartate acting on a cell whose energetic reserves aren’t adequate to sustain the level of activity provoked by the transmitter. Once an excitotoxic state exists, the consequences of cell exhaustion can increase the likelihood that the condition will spread to other cells, since any excitation can trigger a complex of other excitatory processes. As calcium enters cells, potassium leaves, and enzymes are activated, producing free fatty acids (linoleic and arachidonic, for example) and prostaglandins,”

    “Simply getting outside the world of compartmentalized diseases, there is an abundance of evidence showing the variety of ways in which cells can fail. Energy is needed for cell maintenance and adaptation, and the type of fuel used to provide the energy is crucial. Fatty acids interfere with the oxidation of glucose, and this effect can be seen in heart failure, immunodeficiency, dementia, as well as in simple stress, diabetes, and many other simple situations (dementia: Montine and Morrow, 2005; Yaqoob, et al., 1994).”

    “When a muscle or nerve is fatigued, it swells, retaining water. When the swelling is extreme, its ability to contract is limited. Excess water content resembles a partly excited state, in which increase amounts of sodium and calcium are free in the cytoplasm. Energy is needed to eliminate the sodium and calcium, or to bind calcium allowing the cell to extrude excess water and return to the resting state. Thyroid hormone allows cells’ mitochondria to efficiently produce energy, and it also regulates the synthesis of proteins (phospholamban and calcisequestrin) that control the binding of calcium. When the cell is energized, by the mitochondria working with thyroid, oxygen, and sugar, these proteins change their form, binding calcium and removing it from the contractile system, allowing the cell to relax, to be fully prepared for the next contraction. If the calcium isn’t fully and quickly bound, the cell retains extra water and sodium, and isn’t able to fully relax.”

    “Older ways of understanding aging and degenerative disease are now returning to the foreground. The developmental interactions of the organism with its environment, and the interactions of its cells, tissues, and organs with each other, have again become the focus of biological aging research. In place of the old belief that “we are defined and limited by our genes,” the new perspective is showing us that we are limited by our environment, and that our environment can be modified. As we react to unsuitable environments, our internal environments become limiting for our cells, and instead of renewing themselves, repairing damage, and preparing for new challenges, our cells find themselves in blind alleys. Looking at aging in this way suggests that putting ourselves into the right environments could prevent aging.”

    The end product of respiration is carbon dioxide, and it is an essential component of the life process. The ability to produce and retain enough carbon dioxide is as important for longevity as the ability to conserve enough heat to allow chemical reactions to occur as needed.

    Carbon dioxide protects cells in many ways. By bonding to amino groups, it can inhibit the glycation of proteins during oxidative stress, and it can limit the formation of free radicals in the blood; inhibition of xanthine oxidase is one mechanism (Shibata, et al., 1998). It can reduce inflammation caused by endotoxin/LPS, by lowering the formation of tumor necrosis factor, IL-8 and other promoters of inflammation (Shimotakahara, et al., 2008). It protects mitochondria (Lavani, et al., 2007), maintaining (or even increasing) their ability to respire during stress.

    The “replicative lifespan” of a cell can be shortened by factors like resveratrol or estrogen that interfere with mitochondrial production of carbon dioxide. Both of those chemicals cause skin cells, keratinocytes, to stop dividing, to take up calcium, and to begin producing the horny material keratin, that allows superficial skin cells to form an effective barrier. This process normally occurs as these cells differentiate from the basal (stem) cells and, by multiplying, move farther outward away from the underlying blood vessels that provide the nutrients that are oxidized to form carbon dioxide, and as they get farther from the blood supply, they get closer to the external air, which contains less than 1% as much CO2 as the blood. This normally causes their eventual hardening into the keratin cells, but when conditions are optimal, numerous layers of moist, translucent cells that give the skin the characteristic appearance of youth, will be retained between the basal cells and the condensed surface layers. (Wilke, et al., 1988)

    In other types of tissue, a high level of carbon dioxide has a similar stabilizing effect on cells, preserving stem cells, limiting stress and preventing loss of function. In the lining of the mouth, where the oxygen tension is lower, and carbon dioxide higher, the cells don’t form as much keratin as the skin cells do. In the uterus, the lining cells would behave similarly, except that estrogen stimulates keratinization. A vitamin A deficiency mimics an estrogen excess, and can cause excessive keratinization of membrane cells.”

    “Apparently, anything that depletes the cell’s energy, lowering ATP, allows an excess of calcium to enter cells, contributing to their death (Ray, et al., 1994). Increasing intracellular calcium activates phospholipases, releasing more polyunsaturated fats (Sweetman, et al., 1995) The acrolein which is released during lipid peroxidation inhibits mitochondrial function by poisoning the crucial respiratory enzyme, cytochrome oxidase, resulting in a decreased ability to produce energy (Picklo and Montine, 2001). (In the retina, the PUFA contribute to light-induced damage of the energy producing ability of the cells [King, 2004], by damaging the same crucial enzyme.)”


    Inflammatory C-Reactive Protein (CRP)

    June 8th, 2014

    Also see:
    Endotoxin: Poisoning from the Inside Out
    Ray Peat, PhD on Endotoxin
    Exercise and Endotoxemia
    Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)

    “Systemic metabolic problems make local problems worse, and if a local injury is serious, it can cause the liver to produce stress-related proteins called “acute phase proteins,” including fibrinogen and serum amyloids A and P, C-reactive protein, and other inflammation-related proteins. These proteins are a primitive sort of immune system, that· can directly bind to some harmful substances. Endotoxin absorbed from bowel bacteria is probably the commonest reason for increased production of these proteins. The acute phase proteins contribute to the development of tumors in various ways. For example fibrinogen degradation products are pro-inflammatory. Although these are called acute phase proteins, they sometimes might better be called chronic inflammation proteins, since they are associated with diabetes, cancer, and heart disease.” -Ray Peat, PhD

    J Clin Endocrinol Metab. 2001 Sep;86(9):4216-22.
    Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women.
    Herrington DM, Brosnihan KB, Pusser BE, Seely EW, Ridker PM, Rifai N, MacLean DB.
    Although increased levels of C-reactive protein have been linked to E therapy, the significance of this finding and whether it occurs with the selective ER modulators are unknown. Thirty-five healthy postmenopausal women were enrolled in a placebo-controlled, two-period cross-over design trial to evaluate the effects of 0.625 mg oral conjugated E and 60 mg droloxifene, a structural analog of tamoxifen, on serum levels of C-reactive protein, IL-6, and endothelial cell adhesion molecules. E treatment resulted in 65.8% higher levels of C-reactive protein (P = 0.0002) and 48.1% higher levels of IL-6 (P < 0.001), but also resulted in a 10.9% reduction in soluble E-selectin (P = 0.002) and borderline reductions in vascular cell adhesion molecule-1. In contrast, droloxifene had no effect on C-reactive protein and IL-6, but did produce a significant 11% reduction in E-selectin (P < 0.00001). However, droloxifene also resulted in an 11.6% increase in vascular cell adhesion molecule-1 (P < 0.007). These data provide additional evidence of a proinflammatory effect of E that may have adverse cardiovascular consequences. However, these changes were also accompanied by a reduction in E-selectin, suggesting an antiinflammatory effect at the level of the endothelium. The net clinical impact of these changes is not yet well established. In contrast, droloxifene had little or no proinflammatory effects on C-reactive protein and IL-6 and had mixed effects on endothelial adhesion molecules. This observation provides additional rationale for continuing to evaluate the potential cardiovascular benefits of selective ER modulators.

    Am J Pathol. 2001 Mar;158(3):1039-51.
    Generation of C-reactive protein and complement components in atherosclerotic plaques.
    Yasojima K, Schwab C, McGeer EG, McGeer PL.
    C-reactive protein (CRP) and complement are hypothesized to be major mediators of inflammation in atherosclerotic plaques. We used the reverse transcriptase-polymerase chain reaction technique to detect the mRNAs for CRP and the classical complement components C1 to C9 in both normal arterial and plaque tissue, establishing that they can be endogenously generated by arteries. When the CRP mRNA levels of plaque tissue, normal artery, and liver were compared in the same cases, plaque levels were 10.2-fold higher than normal artery and 7.2-fold higher than liver. By Western blotting, we showed that the protein levels of CRP and complement proteins were also up-regulated in plaque tissue and that there was full activation of the classical complement pathway. By in situ hybridization, we detected intense signals for CRP and C4 mRNAs in smooth muscle-like cells and macrophages in the thickened intima of plaques. By immunohistochemistry we showed co-localization of CRP and the membrane attack complex of complement. We also detected up-regulation in plaque tissue of the mRNAs for the macrophage markers CD11b and HLA-DR, as well as their protein products. We showed by immunohistochemistry macrophage infiltration of plaque tissue. Because CRP is a complement activator, and activated complement attacks cells in plaque tissue, these data provide evidence of a self-sustaining autotoxic mechanism operating within the plaques as a precursor to thrombotic events.

    Ital Heart J. 2001 Mar;2(3):196-9.
    C-reactive protein and atherothrombosis.
    Pepys MB, Hirschfield GM.
    Circulating concentrations of C-reactive protein (CRP), the classical acute phase protein and sensitive systemic marker of inflammation, significantly predict atherothrombotic events and outcome after acute myocardial infarction, demonstrating the key role of inflammation in atherosclerosis and its complications. The binding specificity of CRP for low density lipoproteins, for modified low density lipoproteins, and for damaged and dead cells, coupled with the capacity of bound CRP to activate complement, and with the presence of CRP in atheroma and acute myocardial infarction lesions, all suggest a possible pathogenetic role of CRP. Development of drugs to block binding of CRP to its various ligands in vivo will enable this hypothesis to be tested.

    Hypertension. 2004 Jul;44(1):6-11. Epub 2004 May 17.
    C-reactive protein: risk marker or mediator in atherothrombosis?
    Jialal I, Devaraj S, Venugopal SK.
    Inflammation appears to be pivotal in all phases of atherosclerosis from the fatty streak lesion to acute coronary syndromes. An important downstream marker of inflammation is C-reactive protein (CRP). Numerous studies have shown that CRP levels predict cardiovascular disease in apparently healthy individuals. This has resulted in a position statement recommending cutoff levels of CRP <1.0, 1.0 to 3.0, and >3.0 mg/L equating to low, average, and high risk for subsequent cardiovascular disease. More interestingly, much in vitro data have now emerged in support of a role for CRP in atherogenesis. To date, studies largely in endothelial cells, but also in monocyte-macrophages and vascular smooth muscle cells, support a role for CRP in atherogenesis. The proinflammatory, proatherogenic effects of CRP that have been documented in endothelial cells include the following: decreased nitric oxide and prostacyclin and increased endothelin-1, cell adhesion molecules, monocyte chemoattractant protein-1 and interleukin-8, and increased plasminogen activator inhibitor-1. In monocyte-macrophages, CRP induces tissue factor secretion, increases reactive oxygen species and proinflammatory cytokine release, promotes monocyte chemotaxis and adhesion, and increases oxidized low-density lipoprotein uptake. Also, CRP has been shown in vascular smooth muscle cells to increase inducible nitric oxide production, increase NFkappa(b) and mitogen-activated protein kinase activities, and, most importantly, upregulate angiotensin type-1 receptor resulting in increased reactive oxygen species and vascular smooth muscle cell proliferation. Future studies should be directed at delineating the molecular mechanisms for these important in vitro observations. Also, studies should be directed at confirming these findings in animal models and other systems as proof of concept. In conclusion, CRP is a risk marker for cardiovascular disease and, based on future studies, could emerge as a mediator in atherogenesis.

    J Periodontol. 2008 Aug;79(8 Suppl):1544-51. doi: 10.1902/jop.2008.080249.
    Inflammation, C-reactive protein, and atherothrombosis.
    Ridker PM, Silvertown JD.
    Atherothrombosis of the coronary and cerebral vessels is understood to be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. From a vascular biology perspective, the processes of cellular adhesion, monocyte and macrophage attachment, and transmigration of immune cells across the endothelium are crucial steps in early atherogenesis and in the later stages of mature plaque rupture, particularly the transition of unstable plaque at the time of acute thrombosis. There is abundant clinical evidence demonstrating that many biomarkers of inflammation are elevated years in advance of first ever myocardial infarction (MI) or thrombotic stroke and that these same biomarkers are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death. In daily practice, the inflammatory biomarker in widest use is high-sensitivity C-reactive protein (hsCRP); when interpreted within the context of usual risk factors, levels of hsCRP <1, 1 to 3, and >3 mg/l denote lower, average, and higher relative risk for future vascular events. Risk-prediction models that incorporate hsCRP, such as the Reynolds Risk Score, have been developed that improve risk classification and the accuracy for global risk prediction, particularly for those deemed at “intermediate risk” by usual algorithms, such as the Framingham Risk Score. With regard to cerebral vessels, increased biomarkers of inflammation, including hsCRP, have been associated with increased stroke risk as well as an increased rate of atherosclerosis progression in the carotid vessels. Although the proportion of variation in hsCRP explained by genetic factors may be as large as 20% to 40%, diet, exercise, and smoking cessation remain critical tools for risk reduction and CRP reduction. Statin therapy reduces hsCRP in a largely low-density lipoprotein (LDL)-independent manner, and the “anti-inflammatory” properties of these agents have been suggested as a potential mechanism beyond LDL reduction for the efficacy of these agents. The ongoing multinational Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of 17,802 initially healthy men and women with low levels of LDL cholesterol but increased levels of hsCRP will help to define whether vascular protection can be achieved with statin therapy, even in the absence of hyperlipidemia. Targeted anti-inflammatory therapies are being developed that may provide a direct method of translating the biology of inflammation into new clinical treatments across multiple vascular beds. This article summarizes data supporting a role for inflammation in cardiovascular disease and offers the possibility that other disorders characterized by inflammation, such as periodontal disease, may have an indirect role by influencing the risk, manifestation, and progression of vascular events.

    JAMA. 2001 Jul 18;286(3):327-34.
    C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
    Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM.
    Inflammation is hypothesized to play a role in development of type 2 diabetes mellitus (DM); however, clinical data addressing this issue are limited.
    To determine whether elevated levels of the inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) are associated with development of type 2 DM in healthy middle-aged women.
    Prospective, nested case-control study.
    The Women’s Health Study, an ongoing US primary prevention, randomized clinical trial initiated in 1992.
    From a nationwide cohort of 27 628 women free of diagnosed DM, cardiovascular disease, and cancer at baseline, 188 women who developed diagnosed DM over a 4-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls.
    Incidence of confirmed clinically diagnosed type 2 DM by baseline levels of IL-6 and CRP.
    Baseline levels of IL-6 (P<.001) and CRP (P<.001) were significantly higher among cases than among controls. The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 (95% confidence interval [CI], 3.7-15.4) and 15.7 for CRP (95% CI, 6.5-37.9). Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol, and hormone replacement therapy; multivariate relative risks for the highest vs lowest quartiles were 2.3 for IL-6 (95% CI, 0.9-5.6; P for trend =.07) and 4.2 for CRP (95% CI, 1.5-12.0; P for trend =.001). Similar results were observed in analyses limited to women with a baseline hemoglobin A(1c) of 6.0% or less and after adjustment for fasting insulin level. CONCLUSIONS: Elevated levels of CRP and IL-6 predict the development of type 2 DM. These data support a possible role for inflammation in diabetogenesis.

    Thromb Haemost. 1999 Jun;81(6):925-8.
    Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women.
    van Baal WM, Kenemans P, van der Mooren MJ, Kessel H, Emeis JJ, Stehouwer CD.
    To study the short-term effect of unopposed oestradiol (E2) and sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein (CRP) in healthy postmenopausal women.
    Prospective, randomised, placebo-controlled 12-week study. Sixty healthy. normotensive, non-hysterectomised postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at baseline and at 4 and 12 weeks.
    CRP levels increased significantly during the 12 weeks in the E2 and the E2+P groups compared to placebo. No differences were found between the E2 group and the E2+P group [E2 and E2+P group together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a quantitative estimate of the increase, the median change calculated from baseline in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P = 0.08) at 12 weeks, as compared to the placebo group.
    In healthy postmenopausal women, short-term treatment with E2 or E2+P was associated with a rapid rise in CRP concentrations. These observations raise the possibility that the increased risk of cardiovascular events is related to an initial increase in CRP levels after starting hormone replacement therapy.

    Clin J Sport Med. 2001 Jan;11(1):38-43.
    The acute phase response and exercise: the ultramarathon as prototype exercise.
    Fallon KE.
    Controversy exists in relation to the nature of the acute phase response, which is known to occur following endurance exercise. This study was conducted to demonstrate the similarities between this response and the response consequent to general medical and surgical conditions.
    This is a case series field study of serum levels of acute phase reactants in a group of ultramarathon runners competing in a 6-day track race.
    Seven male and one female experienced ultramarathon runners.
    A track race of 6 days duration.
    Serum iron, ferritin, transferrin, albumin, haptoglobin, alpha-1 antitrypsin, complement components 3 and 4, C-reactive protein, and erythrocyte sedimentation rate, total iron binding capacity, and transferrin saturation.
    Of the 11 acute phase reactants measured, 6 (serum iron, ferritin, percent transferrin saturation, C-reactive protein, erythrocyte sedimentation rate, and haptoglobin) responded as if an acute phase response was present; 5 (tranferrin, albumin, alpha-1 antitrypsin, and complement components 3 and 4) did not respond in such a fashion.
    This study provides further evidence that the acute phase response consequent to exercise is analogous to that which occurs in general medical and surgical conditions. The previous demonstration of the presence of the appropriate cytokines following exercise, the findings of others in relation to acute phase reactants not the subjects of this study, the possibility that a training effect leading to attenuation of the response and the realization that the acute phase response is not identical across a range of medical conditions lends weight to the above conclusion.


    “Many types of evidence indicate that environmental PUFA and prostaglandins produced from the “essential” fatty acids are required for inflammation to progress to degeneration. The n-9 polyunsaturated tatty acids (the kind we can make make from saturated fat or sugar) seems to be positively protective against inflammation. For example, rats fed a diet with 2% hydrogenated coconut oil for two weeks had lower levels of IL-6 and C-reactive protein than when a small amount of arachidonic acid and docosahexaenoic acid (DHA) were added. Mead acid (20:3n9) was lower in the group with the PUFA supplement, and the inflammatory reaction to endotoxin was greater in the supplemented group (Ling, et aI., 2012).” -Ray Peat, PhD

    Metabolism. 2012 Mar;61(3):395-406. Epub 2011 Sep 23.
    Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid-deficient diet alters the response to endotoxin in rats.
    Ling PR, Malkan A, Le HD, Puder M, Bistrian BR.
    This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid-deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase-1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.

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    Ray Peat, PhD – Concerns with Starches

    June 6th, 2014

    Also see:
    Collection of Ray Peat Quote Blogs by FPS
    Scanning Electron Microscope (SEM) images of plant cell microparticles in urine sediment
    Fermentable Carbohydrates, Anxiety, Aggression
    Ray Peat, PhD on Low Blood Sugar & Stress Reaction
    Low Blood Sugar Basics
    Belly Fat, Cortisol, and Stress
    Toxicity of Stored PUFA
    PUFA Accumulation & Aging
    PUFA Promote Stress Response; Saturated Fats Suppress Stress Response
    Ray Peat, PhD on the Benefits of the Raw Carrot
    Estrogen, Serotonin, and Aggression
    The effect of raw carrot on serum lipids and colon function
    Protective Bamboo Shoots
    Calcium to Phosphorus Ratio, PTH, and Bone Health
    Carbohydrates and Bone Health
    Calcium Paradox
    Endotoxin-lipoprotein Hypothesis
    Endotoxin: Poisoning from the Inside Out
    Protection from Endotoxin
    Bowel Toxins Accelerate Aging
    Protective Cascara Sagrada and Emodin
    Fermentable Carbohydrates, Anxiety, Aggression
    Intestinal Serotonin and Bone Loss
    Autoimmunity and Intestinal Flora
    Are Happy Gut Bacteria Key to Weight Loss?

    This blog offers a short synopsis of the primary concerns to have with dietary starches. I offer five tips when eating starches at the end of the blog. Italicized quotes are by Ray Peat, PhD.

    Bad picture of a potato.

    Bad picture of a potato.

    1. Because of their glycemia, starches tend to cause blood sugar dysregulation compared to fructose and sugar (sucrose), promoting the effects of adrenaline, cortisol, stored PUFA, endotoxin, and estrogen.

    “If you take orange juice with some fat it will be more stabilizing to your blood sugar than the grits and potatoes. Starches increase the stress hormones, interfering with progesterone and thyroid.”

    “The polyunsaturated fatty acids, which break down into toxic fragments and free radicals and prostaglandin-like chemicals, are–along with bacterial toxins produced in the intestine–the source of the main inflammatory and degenerative problems. Sugar and the minerals in fruits are fairly effective in keeping free fatty acids from being released from our tissues, and the fats we synthesize from them are saturated, and aren’t likely to be stored as excess fat, because they don’t suppress metabolism (as polyunsaturated fats and some amino acids do). The minerals of fruits and milk contribute to metabolic activation, and prevention of free-radical damage.”

    “Rather than the sustained hyperglycemia which is measured for determining the glycemic index, I think the “diabetogenic” or “carcinogenic” action of starch has to do with the stress reaction that follows the intense stimulation of insulin release. This is most easily seen after a large amount of protein is eaten. Insulin is secreted in response to the amino acids, and besides stimulating cells to take up the amino acids and convert them into protein, the insulin also lowers the blood sugar. This decrease in blood sugar stimulates the formation of many hormones, including cortisol, and under the influence of cortisol both sugar and fat are produced by the breakdown of proteins, including those already forming the tissues of the body. At the same time, adrenalin and several other hormones are causing free fatty acids to appear in the blood.”

    “It’s the stored PUFA, released by stress or hunger, that slow metabolism.”

    2. Starches can feed bacteria in the lower portion of the intestines if not digested quickly, increasing intestinal toxin burden and fermentation of carbohydrates which can stress the liver and produce changes in the metabolic rate, mood, and mediators of inflammation (like serotonin, estrogen, endotoxin). Excessive endotoxin exposure affects the liver’s production of cholesterol (not favorable).

    “The upper part of the small intestine is sterile in healthy people. In the last 40 years, there has been increasing interest in the “contaminated small-bowel syndrome,” or the “small intestine bacterial overgrowth syndrome.” When peristalsis is reduced, for example by hypothyroidism, along with reduced secretion of digestive fluids, bacteria are able to thrive in the upper part of the intestine. Sugars are very quickly absorbed in the upper intestine, so starches and fibers normally provide most of the nourishment for bowel bacteria…Thyroid hormone increases digestive activity, including stomach acid and peristalsis, and both thyroid and progesterone increase the ability of the intestine to absorb sugars quickly; their deficiency can permit bacteria to live on sugars as well as starches.”

    “Bacterial endotoxin increases serotonin release from the intestine, and increases its synthesis in the brain (Nolan, et al., 2000) and liver (Bado, 1983). It also stimulates its release from platelets, and reduces the lungs’ ability to destroy it. The formation of serotonin in the intestine is also stimulated by the lactate, propionate and butyrate that are formed by bacteria fermenting fiber and starch, but these bacteria also produce endotoxin. The inflammation-producing effects of lactate, serotonin, and endotoxin are overlapping, additive, and sometimes synergistic, along with histamine, nitric oxide, bradykinin, and the cytokines.”

    “Starches and fibers support bacterial growth and can increase serotonin.”

    “Since cholesterol is the source of progesterone and testosterone (and pregnenolone, DHEA, etc.), and sugar increases it, having fruit rather than starch might increase the hormones. Those hormones, antagonistic to cortisol, can help to reduce waist fat.”

    “Sugar helps the liver to make cholesterol, switching from starchy vegetables to sweet fruits will usually bring cholesterol levels up to normal.”

    “Besides avoiding foods containing fermentable fibers and starches that resist quick digestion, eating fibrous foods that contain antibacterial chemicals, such as bamboo shoots or raw carrots, helps to reduce endotoxin and serotonin.”

    “Bacteria thrive on starches that aren’t quickly digested, and the bacteria convert the energy into bulk, and stimulate the intestine. (But at the same time, they are making the toxins that affect the hormones.)”

    “Polysaccharides and oligosaccharides include many kinds of molecules that no human enzyme can break down, so they necessarily aren’t broken down for absorption until they encounter bacterial or fungal enzymes. In a well maintained digestive system, those organisms will live almost exclusively in the large intestine, leaving the length of the small intestine for the absorption of monosaccharides without fermentation. When digestive secretions are inadequate, and peristalsis is sluggish, bacteria and fungi can invade the small intestine, interfering with digestion and causing inflammation and toxic effects.”

    3. Starches tend to be more fattening than sugar because of their effect on blood sugar and insulin. A starchy diet in conjunction with the consumption of polyunsaturated fats is a reliable way to produce obesity.

    “When the idea of “glycemic index” was being popularized by dietitians, it was already known that starch, consisting of chains of glucose molecules, had a much higher index than fructose and sucrose. The more rapid appearance of glucose in the blood stimulates more insulin, and insulin stimulates fat synthesis, when there is more glucose than can be oxidized immediately. If starch or glucose is eaten at the same time as polyunsaturated fats, which inhibit its oxidation, it will produce more fat. Many animal experiments show this, even when they are intending to show the dangers of fructose and sucrose.”

    “Starch is less harmful when eaten with saturated fat, but it’s still more fattening than sugars.”

    “Starch and glucose efficiently stimulate insulin secretion, and that accelerates the disposition of glucose, activating its conversion to glycogen and fat, as well as its oxidation. Fructose inhibits the stimulation of insulin by glucose, so this means that eating ordinary sugar, sucrose (a disaccharide, consisting of glucose and fructose), in place of starch, will reduce the tendency to store fat. Eating “complex carbohydrates,” rather than sugars, is a reasonable way to promote obesity. Eating starch, by increasing insulin and lowering the blood sugar, stimulates the appetite, causing a person to eat more, so the effect on fat production becomes much larger than when equal amounts of sugar and starch are eaten. The obesity itself then becomes an additional physiological factor; the fat cells create something analogous to an inflammatory state. There isn’t anything wrong with a high carbohydrate diet, and even a high starch diet isn’t necessarily incompatible with good health, but when better foods are available they should be used instead of starches. For example, fruits have many advantages over grains, besides the difference between sugar and starch. Bread and pasta consumption are strongly associated with the occurrence of diabetes, fruit consumption has a strong inverse association.”

    “When starch is well cooked, and eaten with some fat and the essential nutrients, it’s safe, except that it’s more likely than sugar to produce fat, and isn’t as effective for mineral balance.”

    “Per calorie, sugar is less fattening than starch, partly because it stimulates less insulin, and, when it’s used with a good diet, because it increases the activity of thyroid hormone.”

    “In an old experiment, a rat was tube-fed ten grams of corn-starch paste, and then anesthetized. Ten minutes after the massive tube feeding, the professor told the students to find how far the starch had moved along the alimentary canal. No trace of the white paste could be found, demonstrating the speed with which starch can be digested and absorbed. The very rapid rise of blood sugar stimulates massive release of insulin, and rapidly converts much of the carbohydrate into fat.”

    4. Starches lack fructose. Fructose helps raise the metabolic rate and regulate insulin secretion.

    “Starch is the only common carbohydrate that contains no fructose.”

    “Here’s a currently often cited article which claimed to show that fructose causes ‘insulin resistance’ compared to a starch diet, but careful reading would show that it confirms the powerful protective effect of fructose (and sucrose), since if the greater weight gain of the starch eaters continued beyond the short 5 weeks of the experiment, after a year the starchy rats would have weighed twice as much as the lean sugar eaters. The fructose limits insulin secretion, but intensifies metabolism, burning calories faster.”

    5. Starch can irritate the gut lining, and starch granules can enter the bloodstream and urine (persorption) inappropriately. Chronic irritation of the gut lining makes serotonin, endotoxin, nitric oxide, and estrogen serious threats to the metabolism, the liver, and overall well being. Persorption promotes tissue injury and circulatory issues.

    “Persorption refers to a process in which relatively large particles pass through the intact wall of the intestine and enter the blood or lymphatic vessels. It can be demonstrated easily, but food regulators prefer to act as though it didn’t exist. The doctrine that polymers–gums, starches, peptides, polyester fat substitutes–and other particulate substances can be safely added to food because they are “too large to be absorbed” is very important to the food industry and its shills.

    When the bowel is inflamed, toxins are absorbed. The natural bacterial endotoxin produces many of the same inflammatory effects as the food additive, carrageenan. Like inflammatory bowel disease, the incidence of liver tumors and cirrhosis has increased rapidly. Liver damage leads to hormonal imbalance. Carrageenan produces inflammation and immunodeficiency, synergizing with estrogen, endotoxin and unsaturated fatty acids.”

    “In the presence of bacterial endotoxin, respiratory energy production fails in the cells lining the intestine. Nitric oxide is probably the main mediator of this effect.”

    “Intestinal inflammation is often behind recurrent tooth infectons, and a daily raw carrot can make a big difference (along with avoiding legumes, undercooked starches and raw or undercooked vegetables).”

    “Volkheimer found that mice fed raw starch aged at an abnormally fast rate, and when he dissected the starch-fed mice, he found a multitude of blocked arterioles in every organ, each of which caused the death of the cells that depended on the blood supplied by that arteriole. It isn’t hard to see how this would affect the functions of organs such as the brain and heart, even without considering the immunological and other implications….”

    “Tiny particles of insoluble materials — clay, starch, soot, bacteria — are all potential sources of serious inflammatory reactions, and the ultra-small particles are potentially ultra-numerous and harder to avoid.”

    “Around 1988 I read Gerhard Volkheimer’s persorption article, and after doing some experiments with tortillas and masa, I stopped eating all starch except for those, then eventually I stopped those. Besides grains of starch entering the blood stream, lymph, and cerebral spinal fluid, starch feeds bacteria, increasing endotoxin and serotonin.”

    “For people with really sensitive intestines or bad bacteria, starch should be zero.”

    6. In some cases, they are high in phosphorus relative to calcium as in grains, beans, and legumes. Sugar is more friendly on mineral balance and bone health relative to starch.

    “The foods highest in phosphate, relative to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added phosphate. Foods with a higher, safe ratio of calcium to phosphate are leaves, such as kale, turnip greens, and beet greens, and many fruits, milk, and cheese.”

    “When starch is well cooked, and eaten with some fat and the essential nutrients, it’s safe, except that it’s more likely than sugar to produce fat, and isn’t as effective for mineral balance.”

    7. Some are reactive to starches, like the potato, because they are nightshade vegetables.

    “When a person has limited money for food, potatoes are a better staple than beans or oats. Starches associated with saponins, alkaloids, and other potentially pro-inflammatory things make them a less than ideal food, if you have digestion-related health problems, and if you can afford to choose. New potatoes are tastier, less starchy, and probably less likely to cause digestive irritation.”

    Help with Starches:
    1. Gauge your individual reaction to starches vs. sugar. This can take some trial and error. You may find that one helps more than the other in raising the metabolic rate or keeping your metabolic rate up or that having both in your diet is more helpful than either alone.
    2. Combine cooked-starches with a animal protein and plenty of saturated fat, like butter. The saturated fat blunts the glycemia of the starches and has anti-microbial effects in the intestines. I boil white potatoes for 40 minutes when making mashed potatoes. I then add butter, salt, and milk for taste and appropriate consistency. Shorter boiling times for me causes intestinal gas. For those that have an allergic reaction to potatoes, in addition to cooking well, skin removal is another step to take to avoid a reaction.
    3. Eat a diet that is in favor of the more digestible, micronutrient rich, blood-sugar friendly, sweet-tasting carbohydrates from ripe or cooked fruits, fresh orange juice, milk, and honey. If bowel toxins accelerate the aging process, then a health-preserving diet is low in starch. Additionally, the realities of the persorption of starch granules is a systemic concern that needs further attention considering the amount of starch in the SAD diet from the likes of grains/flour, beans, legumes, and corn.
    4. Well-cooked below-ground vegetables, masa harina, and hominy are some of the best starches to consume. The younger versions of below-ground vegetables (i.e. new potatoes or baby beets for example) contain less starch and more sugar compared to the mature plants. White potatoes are a good source of protein especially for vegetarians.
    5. If you react well to supplemental powdered fructose, it can be used along side starch-containing meals as a means to regulate blood sugar and encourage liver-glycogen storage and efficient glucose use.


    Coffee Done Right – Tips to Help Avoid Coffee Intolerance

    June 4th, 2014

    Also see:
    Diet, nutrition, physical activity and liver cancer
    Caffeine: A vitamin-like nutrient, or adaptogen by Ray Peat, PhD
    Coffee Inhibit Iron Absorption
    Low Blood Sugar Basics
    Ray Peat, PhD on Low Blood Sugar & Stress Reaction
    Stress – A Shifting of Resources
    Sugar (Sucrose) Restrains the Stress Response
    Hope for Hypoglycemia: It’s Not Your Mind, It’s Your Liver by Broda Barnes, MD, PhD
    Chronic caffeine intake decreases circulating catecholamines and prevents diet-induced insulin resistance and hypertension in rats.

    Potent Stimulator
    Coffee is a potent metabolic stimulator and must be viewed as such. The caffeine in coffee is powerful and can act like thyroid to increase your metabolic rate and the oxidation of sugar, making it a health-protective food. Coffee also has supportive nutrients in the form of B vitamins and magnesium and is a welcome companion to meat-containing meals for adults since it helps inhibit iron absorption.

    These characteristics make coffee a useful tool in your health toolbox provided that you’re taking the right steps to maximize effectiveness. This blog describes what to expect when you’re doing coffee the right way and offers a handful of tips to help if you’re “coffee intolerant.” The blog is written in the context of health promotion rather than one centered solely around body composition and fat loss.

    Self Awareness
    Symptoms to expect when you do coffee right are calmness, focus, motivation, warmth, and stable energy. Coffee done wrong leads to anxiety, shakiness, sweating, feeling wired, inability to focus, and sometimes cold extremities. Truthfully there is no right or wrong because whether you react well or not, the situation serves as a learning tool if you’re knowledgeable and aware enough to assess and correct the symptoms.

    If you do get unfriendly symptoms from using coffee, stop what you’re doing as soon as possible and correct by eating or drinking something sweet like orange juice, honey, a ripe fruit, ice cream, or sweetened milk. This action will lower the symptom-producing substances by raising the blood sugar.

    Stepping on the Gas Pedal
    The metabolic stimulation from coffee ingestion increases the metabolism, which is very friendly, if the metabolic support is adequate. Metabolic stimulators must be matched with adequate metabolic support, especially adequate blood glucose. The common symptom of feeling anxious or shaky after coffee consumption is from a lack of support, which causes low blood sugar (hypoglycemia).

    RT Nokia_001452

    When you drink coffee, the glucose in the bloodstream is used as the caffeine stimulates the body’s metabolism. Coffee is like stepping on the gas pedal in your car. When the fuel system delivers fuel to the engine in adequate amounts, the engine performs well and the car takes off in relation to the intensity of the pressure on the pedal. However, if the fuel system is faulty in some fashion, the engine sputters and is sluggish. For us, the inadequate support from our “fuel system” shows up as unfavorable symptoms as the stress response is activated.

    Problems with coffee begin when our body cannot provide enough fuel for cells given the level of stimulation. If too much stimulation occurs, a stress alarm is signaled that mobilizes resources to provided energy to cells. Your body is saying, “we’ve got lots of stimulation going on here; we need to mobilize resources right now.”

    The stress alarm’s basic function is to raise the blood sugar. This involves the release of glycogen from the liver under the direction of adrenaline and glucagon, and the conversion of the body’s protein (skin, muscles, thymus gland) into glucose using the liver’s help. Cortisol directs this conversion of protein into glucose. The liver is intimately involved in blood sugar regulation.

    Stimulation Requires Support
    Your goal is to avoid the stress alarm from inadequacy of support. The first basic rule is to have coffee with a meal. This delays entry of the caffeine into the bloodstream providing a time-release type effect. A meal is comprised of a protein from an animal and carbohydrate from a plant. Usually animal proteins also contain dietary fat, preferably saturated fat.

    Secondly, add sugar or honey and milk, or sugar or honey and cream to the coffee as an additional buffer against low blood sugar. These step ensures that you are providing the fuel necessary to match the press of your metabolic gas pedal. The amounts of each added ingredient will vary from person to person and comes with practice. Keep in mind that the amounts can change over time and in relation to your mental or physical demands.

    Thirdly, do not have coffee on an empty stomach or immediately upon waking. At these times, you likely do not have the support needed to match the stimulation. You want to avoid activating the stress systems, not encourage their activation through inappropriate choices. For those who wake and aren’t feeling hungry but have the habit of having coffee prior to eating anything, this practice tends to prolong the effects of blood-sugar relating stress hormones which preferably you want to decrease, and not increase, upon rising.

    Lastly, be aware that the hotter the coffee is the more stimulating it tends to be. If you’re susceptible to low blood sugar from drinking hot coffee, follow the aforementioned rules in conjunction with drinking cooler coffee.

    I’ve found that each person seems to have his/her cut-off time in regard to consuming coffee without affecting his/her sleep. When I have coffee after 5 pm, it affects my ability to fall asleep easily at night. Find out what time “last call” is for you through trial and error.


    Coffee Intolerance
    Your “coffee tolerance” can be used as a barometer to measure health progression or lack there of. If you improve your tolerance to coffee, you’re likely headed in the right direction nutritionally. If this doesn’t happen, it could be time to reassess your strategies.

    When your coffee tolerance is poor, it might say that the liver is suffering and is not storing glycogen very well and can’t back you up efficiently (by releasing glycogen) when there is excessive stimulation from coffee. It could also be a signal that you’re not following one or more of the rules listed in the previous section of this blog.

    Hypothyroidism increases susceptibility to low blood sugar because of the effects of thyroid hormone on the liver. Hypothyroid individuals can have coffee intolerance symptoms for this reason and sometimes need to show extra caution when drinking coffee. Broda Barnes’ book “Hypoglycemia: It’s Not Your Mind, It’s Your Liver” is an excellent resource to explore this topic further.

    Going the extra mile is sometimes necessary for those that are really susceptible to over stimulation from coffee. One such step is adding a little coffee to milk/sugar instead of adding milk/sugar to coffee. As you improve, you will be able to handle more coffee and progressively be less dependent upon support — you will be able to press harder on the metabolic gas pedal. Another option is sipping a little coffee with support throughout the day so you get a little stimulation without it being excessive.

    Improved tolerance to coffee may also be accompanied by improvement in other things like sleep quality, energy levels, digestion, cravings, time to fatigue, calmness, and duration that you can comfortably go between meals. As the metabolic rate rises from consistent coffee consumption, the need for all nutrient increases so a sensible diet should consist of foodstuff that offer dense nutrition with few digestive inhibitors (such as ripe fruits, milk, eggs, shellfish, beef liver) rather than nutrient deficient foods (such as pasta, bread, cereals, packaged foods) or hard to digest foods (like raw vegetables, beans, nuts, and legumes).


    “Often, a woman who thinks that she has symptoms of hypoglycemia says that drinking even the smallest amount of coffee makes her anxious and shaky. Sometimes, I have suggested that they try drinking about two ounces of coffee with cream or milk along with a meal. It’s common for them to find that this reduces their symptoms of hypoglycemia, and allows them to be symptom-free between meals.

    …In animal experiments that have been used to argue that pregnant women shouldn’t drink coffee, large doses of caffeine given to pregnant animals retarded the growth of the fetuses. But simply giving more sucrose prevented the growth retardation. Since caffeine tends to correct some of the metabolic problems that could interfere with pregnancy, it is possible that rationally constructed experiments could show benefits to the fetus from the mother’s use of coffee, for example by lowering bilirubin and serotonin, preventing hypoglycemia, increasing uterine perfusion and progesterone synthesis, synergizing with thyroid and cortisol to promote lung maturation, and providing additional nutrients.” -Ray Peat, PhD


    Stress — A Shifting of Resources

    May 25th, 2014

    Also see:
    Collection of FPS Charts
    Low Carb Diet – Death to Metabolism
    Can Endurance Sports Really Cause Harm? The Lipopolysaccharides of Endotoxemia and Their Effect on the Heart
    Running on Empty
    Exercise and Endotoxemia
    Ray Peat, PhD on Endotoxin
    Endotoxin: Poisoning from the Inside Out
    Ray Peat, PhD: Quotes Relating to Exercise
    Ray Peat, PhD and Concentric Exercise
    Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise
    Bowel Toxins Accelerate Aging
    Exercise Induced Stress
    Carbohydrate Lowers Exercise Induced Stress
    Sugar (Sucrose) Restrains the Stress Response
    Low Blood Sugar Basics
    Ray Peat, PhD on Low Blood Sugar & Stress Reaction
    Arachidonic Acid’s Role in Stress and Shock
    Blood Sugar – Resistance to Allergy and Shock
    Shock Increases Estrogen
    A long childhood feeds the hungry human brain

    Your body manages its resources in relation to need. The chart below attempts to provide a visual of the manipulation of resources that occurs during stress.

    Our physiology is designed to handle occasional stressors, but if the stressors are frequent or elevated in intensity then expect adverse consequences eventually. We can only borrow from other areas of the body to nourish others in a time of need so many times until the adaptive systems break down.

    When the adaptive systems do break down, we experience symptoms of some sort. The symptoms are usually a result of a prolonged problem so have patience when attempting to correct them.

    fps shift stress

    Supporting Quotes:
    “Digestion is quickly shut down during stress…The parasympathetic nervous system, perfect for all that calm, vegetative physiology, normally mediates the actions of digestion. Along comes stress: turn off parasympathetic, turn on the sympathetic, and forget about digestion.” -Robert Sapolsky

    Quotes by Ray Peat, PhD:
    “During moderate exercise, adrenalin causes increased blood flow to both the heart and the skeletal muscles, while decreasing the flow of blood to other organs. The increased circulation carries extra oxygen and nutrients to the working organs, while the deprivation of oxygen and glucose pushes the other organs to a catabolic balance. This simple circulatory pattern achieves to some extent the same kind of redistribution of resources, acutely, that is achieved in more prolonged stress by the actions of the glucocorticoids and their antagonists.”

    “The intestine really is where people should be paying more attention because any kind of stress or shock reduces circulation to your intestine, and that makes it more permeable or “leaky”. And aspirin incidentally is now being studied as possibly the best defense against a leaky intestine, even though there is a tremendous amount of Tylenol-type propaganda saying “Don’t use aspirin, it makes your intestine leak”, but, in fact, it prevents endotoxin and bacterial movement from your intestine into your bloodstream.” (interview)

    ‎”Incidental stresses, such as strenuous exercise combined with fasting (e.g., running or working before eating breakfast) not only directly trigger the production of lactate and ammonia, they also are likely to increase the absorption of bacterial endotoxin from the intestine. Endotoxin is a ubiquitous and chronic stressor. It increases lactate and nitric oxide, poisoning mitochondrial respiration, precipitating the secretion of the adaptive stress hormones, which don’t always fully repair the cellular damage.”

    “Bacterial endotoxin causes some of the same effects as adrenalin. When stress reduces circulation to the bowel, causing injury to the barrier function of the intestinal cells, endotoxin can enter the blood, contributing to a shock state, with further impairment of circulation.”

    “The amount of injury needed to increase the endotoxin in the blood can be fairly minor. Two thirds of people having a colonoscopy had a significant increase in endotoxin in their blood, and intense exercise or anxiety will increase it. Endotoxin activates the enzyme that synthesizes estrogen while it decreases the formation of androgen (Christeff, et aI., 1992), and this undoubtedly is partly responsible for the large increases in estrogen in both men and women caused by trauma, sickness or excessive fatigue.”

    “Our innate immune system is perfectly competent for handling our normal stress induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats. The brain has a very high concentration of complex fats, and is highly susceptible to the effects of lipid peroxidative stress, which become progressively worse as the unstable fats accumulate during aging.”


    Charts: Mean SFA, MUFA, & PUFA Content of Various Dietary Fats

    April 9th, 2014

    Also see:
    Polyunsaturated Fatty Acid Content of Cosmetic Oils
    Collection of FPS Charts
    Collection of Ray Peat Quote Blogs by FPS
    Fats and Oils: The significance of temperature
    Master List – Ray Peat, PhD Interviews
    PUFA Accumulation & Aging
    Unsaturated Fats and Longevity
    “Curing” a High Metabolic Rate with Unsaturated Fats
    Fat Deficient Animals – Activity of Cytochrome Oxidase
    Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
    Toxicity of Stored PUFA
    PUFA, Development, and Allergy Incidence
    PUFA, Aging, Cytochrome Oxidase, and Cardiolipin
    Calorie Restriction, PUFA, and Aging
    Errors in Nutrition: Essential Fatty Acids
    Dietary Fats, Temperature, and Your Body
    The Coconut Wars

    SFA = Saturated fatty acids
    MUFA = Monunsaturated fatty acids
    PUFA = Polyunsaturated fatty acids

    Based on decades of research by Ray Peat, PhD, FPS encourages consuming foods with the highest ratio of SFA to PUFA. The SFA:PUFA (S/P) ratio of common dietary fats is shown in the third chart on this page. On that chart, the fats appearing highest on the list are the most health protective.

    The information in the charts below was compiled with the help of a government resource that is available in full by searching for the source provided on the documents. Eggs and dairy foods are not included in this chart because I could not locate the information from the same source on the internet.

    Sorted by Mean Percentage of Polyunsaturated Fatty Acids (PUFA) - Highest to Lowest

    Sorted by Mean Percentage of Polyunsaturated Fatty Acids (PUFA) – Highest to Lowest

    Sorted by Mean Percentage of Saturated Fatty Acids (SFA) - Highest to Lowest

    Sorted by Mean Percentage of Saturated Fatty Acids (SFA) – Highest to Lowest

    Sorted by SFA%:PUFA% Ratio - Highest to Lowest (Most Safe to Least Safe)

    Sorted by SFA%:PUFA% Ratio – Highest to Lowest
    (Most Safe to Least Safe)

    1 Comment "

    Women: Running into Trouble

    March 28th, 2014

    Also see:
    rethink how you exercise: An interview with Rob Turner Part 1
    rethink how you exercise: An interview with Rob Turner Part 2
    Components of Daily Energy Expenditure
    Metabolic testing for athletes and couch potatoes
    Exercise and Effect on Thyroid Hormone
    Exercise Induced Stress
    Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise
    Exercise Induced Menstrual Disorders
    Ray Peat, PhD: Quotes Relating to Exercise
    Ray Peat, PhD and Concentric Exercise
    Overtraining, Undereating & Self-Inflicted Hypothyrodism: Thresholds for Low T3 and High Reverse T3 Levels at 8% & 15% Reduced Energy Intake + Exercise After Only 4 Days!
    Running on Empty

    Women: Running into Trouble

    John Kiefer

    Published: November 7, 2011Posted in: Strong(her)TrainingTags: 

    Women: Running into Trouble

    When I look at the fat guy in the gym wasting his time on forearm curls to lose weight, I don’t feel sympathy. The big tough guy getting stapled to the bench by 365 pounds, when just a second ago he couldn’t even handle 315 pounds — nope, no sympathy there either. The girl who spends thirty minutes bouncing between the yes-no machines (abductor and adductor machines), who is going to have trouble walking the next day — I can’t muster even an iota of pathos. Nobody told them to do these things. But then I watch my friend, Jessica, running on the treadmill, day after day, year after year, running like a madwoman and going nowhere. Her body seems to get softer with every mile and the softer she gets the more she runs. I do feel pity for her because everybody, everywhere has convinced her that running is the way to stay slim and toned.

    There’s a Jessica in every gym and spotting one is easy. The woman that runs for an hour or more every day on the treadmill, who every month or so sets a new distance or time goal. Maybe the goal encompasses the treadmill workouts; maybe it will be her fifth fund-raising marathon; or maybe she’s competing with runners in Finland via Nike®. The goal doesn’t matter, because years of seeing her on the treadmill exposes the results: she’s still — I’m not going to sugar coat this — fat. Or worse, she’s fatter.

    I tried to rescue my Jessica from the clutches of the cardio contingent, but to no avail until a month ago when she called to tell me that a blood test had confirmed her doctor’s suspicion: she had hypothyroidism — her body no longer made enough thyroid hormone. Her metabolism slowed to a snail’s pace and the fat was accumulating. Now she had a culprit to blame, it wasn’t the cardio causing her problems, it was her body rebelling. When Jessica asked my advice, I told her to do two things: schedule a second test for two weeks later and until then, stop all the goddamn running.

    Don’t assume I’m picking on women or making fun. There are men out there who do the same, thinking cardio wipes away the gut resulting from regular weekend beer binges, but they are, in comparison, rare. I am targeting women for three very good reasons:

    1. They are often intensely recruited for fund-raisers like Team-In-Training, lured by the promise of slim, trim health resulting from the month of cardio training leading to a marathon in addition to helping the charity in question
    2. Some physique coaches prescribe 20-plus hours per week of pre-contest cardio for women (that’s a part-time job)
    3. Steady-state endurance activities like this devastate a woman’s metabolism. It will devastate a man’s too, but in different ways.

    There’s not much I hate in the fitness world — well, that’s not true, I hate most things about its present state, but at the top of the list is over-prescribed cardio. I’m not talking about walking or even appropriate HIIT cardio, but the running, cycling, stair climbing or elliptical variety done for hours at or above 65 percent of max heart rate, actually anaerobic threshold is a better measure, but not practical for day-to-day use.

    Trashing steady-state cardio is nothing new and the better of the physique gurus figured this out a long time ago, but even then, they only apply the no-steady-state-cardio rule to contest preparation. The non-cardio coaches fail to state the most detrimental effect, one that applies specifically to women and is a primary reason many first-time or second-time figure and bikini competitors explode in weight when returning to their normal diet. It’s the same reason the Jessicas of the world run for hours per week with negative results. Studies demonstrate beyond any doubt that in women, cardio chronically shuts down the production of the thyroid hormone, T3.1-11

    T3 is the body’s preeminent regulator of metabolism by throttling the efficiency of cells.12-19 T3 acts in various ways to increase heat production.20-21 As I pointed out, in Logic Does Not Apply: A Calorie Is A Calorie, this is one reason using static equations to perform calorie-in, calorie-out weight loss calculations doesn’t work—well, that’s why it’s stupid, actually. When T3 levels are normal, the body burns enough energy to stay warm and muscles function at moderate efficiency. Too much thyroid hormone (hyperthyroidism) and the body becomes inefficient making weight gain almost impossible. Too little T3 (hypothyroidism) and the body accumulates body fat with ease, almost regardless of physical activity level.

    Women unknowingly put themselves into the hypothyroid condition because they perform so much steady-state cardio. In the quest to lose body fat, T3 levels can grant success or a miserable failure because of how it influences other fat-regulating hormones.22-31 In addition, women get all the other negative effects, which I’ll get to. Don’t be surprised or aghast. It’s a simple, sensible adaption of the body, especially a body equipped to bear the full brunt of reproducing.

    Think about it this way: the body is a responsive, adaptive machine evolved for survival. If running on a regular basis, the body senses excessive energy expenditure and adjusts to compensate. Remember, no matter what dreamy nonsense we invent about how we hope the body works, its endgame is always survival. Start wasting energy running and the body reacts by slowing the metabolism to conserve energy. Decreasing energy output is biologically savvy for the body: survive longer while doing this stressful, useless activity — as the body views it. Decreasing T3 production, increases efficiency and adjusts metabolism to preserves energy quickly.

    Nothing exemplifies this increasing efficiency better than how the body starts burning fuel. Training at a consistently plus-65 percent heart rate adapts the body to save as much body fat as possible. That’s right, after regular training, fat cells stop releasing fat during moderate-intensity activities like they once did.32-33 Energy from body fat stores decreases by a whopping 30 percent. 34-35 To this end, the body even sets into motion a series of reactions that make it difficult for muscle to burn fat at all.36-41 Instead of burning body fat, the body is taking extraordinary measures to hold on to it. Still believe cardio is the fast track to fat loss?

    But wait. By acting now, you too can lose muscle mass. That’s right. No more muscle because too much steady-state cardio triggers the loss of muscle.42-45 This seems to be a two-fold mechanism, with heightened and sustained cortisol levels triggering muscle loss,46-56 which upregulates myostatin, a potent destroyer of muscle tissue.57 Oh yeah — say good bye to bone density too — it declines with the muscle mass and strength.58-64 And long-term health? Out the window as well. The percentage of muscle mass is an independent indicator of health.65 Lose muscle, lose bone, lose health—all in this nifty little package.

    When sewn together, these phenomena coordinate a symphony of fat gain for most female competitors post-figure contest. After a month—or three—of cardio surpassing the 20 hours-per-week mark, fat-burning is at an astonishing low, and fat cells await an onslaught of calories to store.66-72 The worst thing imaginable in this state would be to eat whatever you wanted as much as you wanted. The combination of elevated insulin and cortisol would not only make you fat, but creates new fat cells so that you can become fatter than ever.73-80

    I won’t name names, but I have seen amazing displays of gluttony from the smallest, trimmest women. Entire pizzas disappear leaving only the flotsam of toppings that fell during the feeding frenzy; appetizer, meal, cocktails, dessert—a paltry 4000 calories at The Cheesecake Factory vanish as the wait staff delivers each. A clean plate for each return to the buffet — hell with that, the only thing they’re taking to the food bar is a spoon and they’re not coming back. There are no leftovers; there are no crumbs. Some women catch it in time and stop the devastation, but others quickly swell and realize that the supposed off-season look has become their every-season look. And guess what they do to fix it: cardio for an hour every morning and another in the evening to hasten things…

    The “cardio craze” — and it is a form of insanity — is on my hit list and I’m determined to kill it. I don’t know what else I can say. There are better ways to lose fat, be sexy and skinny for life, better ways to prepare for the stage. Women, you need to get off the damn treadmill; I don’t care what you’re preparing for. Stop thinking a bikini-body is at the end of the next marathon or on the other side of that stage. It’s not if you use steady-state cardio to get there — quite the opposite. The show may be over, the finish line might be crossed, but the damage to your metabolism is just starting.

    Don’t want to stop running, fine. At the very least stop complaining about how the fat won’t come off the hips and thighs or the ass. You’re keeping it there.

    What about Jessica, my friend who’s dilemma spawned this article? Luckily she took my suggestion and cut the cardio. Two weeks later, her T3 count was normal. Who would have guessed?

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    2.     Boyden TW, Pamenter RW, Rotkis TC, Stanforth P, Wilmore JH. Thyroidal changes associated with endurance training in women. Med Sci Sports Exerc. 1984 Jun;16(3):243-6.

    3.     Wesche MF, Wiersinga WM. Relation between lean body mass and thyroid volume in competition rowers before and during intensive physical training. Horm Metab Res. 2001 Jul;33(7):423-7.

    4.     Tremblay A, Poehlman ET, Despres JP, Theriault G, Danforth E, Bouchard C. Endurance training with constant energy intake in identical twins: changes over time in energy expenditure and related hormones. Metabolism. 1997 May;46(5):499-503.

    5.     Rone JK, Dons RF, Reed HL. The effect of endurance training on serum triiodothyronine kinetics in man: physical conditioning marked by enhanced thyroid hormone metabolism. Clin Endocrinol (Oxf). 1992 Oct;37(4):325-30.

    6.     Loucks AB, Callister R. Induction and prevention of low-T3 syndrome in exercising women. Am J Physiol. 1993 May;264(5 Pt 2):R924-30.

    7.     Loucks AB, Heath EM. Induction of low-T3 syndrome in exercising women occurs at a threshold of energy availability. Am J Physiol. 1994 Mar;266(3 Pt 2):R817-23.

    8.     Rosolowska-Huszcz D. The effect of exercise training intensity on thyroid activity at rest. J Physiol Pharmacol. 1998 Sep;49(3):457-66.

    9.     Wirth A, Holm G, Lindstedt G, Lundberg PA, Bjorntorp P. Thyroid hormones and lipolysis in physically trained rats. Metabolism. 1981 Mar;30(3):237-41.

    10.  Opstad PK, Falch D, Oktedalen O, Fonnum F, Wergeland R. The thyroid function in young men during prolonged exercise and the effect of energy and sleep deprivation. Clin Endocrinol (Oxf). 1984 Jun;20(6):657-69.

    11.  Hohtari H, Pakarinen A, Kauppila A. Serum concentrations of thyrotropin, thyroxine, triiodothyronine and thyroxine binding globulin in female endurance runners and joggers. Acta Endocrinol (Copenh). 1987 Jan;114(1):41-6.

    12.  Lanni A, Moreno M, Lombardi A, Goglia F. Thyroid hormone and uncoupling proteins. FEBS Lett. 2003 May 22;543(1-3):5-10. Review.

    13.  Leijendekker WJ, van Hardeveld C, Elzinga G. Heat production during contraction in skeletal muscle of hypothyroid mice. Am J Physiol. 1987 Aug;253(2 Pt 1):E214-20.

    14.  Silva JE. Thyroid hormone control of thermogenesis and energy balance. Thyroid. 1995 Dec;5(6):481-92. Review.

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    18.  Schrauwen P, Hesselink M. UCP2 and UCP3 in muscle controlling body metabolism. J Exp Biol. 2002 Aug;205(Pt 15):2275-85. Review.

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    20.  Goglia F, Silvestri E, Lanni A. Thyroid hormones and mitochondria. Biosci Rep. 2002 Feb;22(1):17-32. Review.

    21.  Goglia F, Moreno M, Lanni A. Action of thyroid hormones at the cellular level: the mitochondrial target. FEBS Lett. 1999 Jun 11;452(3):115-20. Review.

    22.  Ribeiro MO, Carvalho SD, Schultz JJ, Chiellini G, Scanlan TS, Bianco AC, Brent GA. Thyroid hormone–sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform–specific. J Clin Invest. 2001 Jul;108(1):97-105.

    23.  Beylot M, Riou JP, Bienvenu F, Mornex R. Increased ketonaemia in hyperthyroidism. Evidence for a beta-adrenergic mechanism. Diabetologia. 1980;19(6):505-10.

    24.  Ostman J, Arner P, Bolinder J, Engfeldt P, Wennlund A. Regulation of lipolysis in hyperthyroidism. Int J Obes. 1981;5(6):665-70.

    25.  Collins S, Cao W, Daniel KW, Dixon TM, Medvedev AV, Onuma H, Surwit R. Adrenoceptors, uncoupling proteins, and energy expenditure. Exp Biol Med (Maywood). 2001 Dec;226(11):982-90.

    26.  Williams LT, Lefkowitz RJ, Watanabe AM, Hathaway DR, Besch HR Jr. Thyroid hormone regulation of beta-adrenergic receptor number. J Biol Chem. 1977 Apr 25;252(8):2787-9.

    27.  Martin WH 3rd. Triiodothyronine, beta-adrenergic receptors, agonist responses, and exercise capacity. Ann Thorac Surg. 1993 Jul;56(1 Suppl):S24-34.

    28.  Tsujimoto G, Hashimoto K, Hoffman BB. Effects of thyroid hormone on beta-adrenergic responsiveness of aging cardiovascular systems. Am J Physiol. 1987 Mar;252(3 Pt 2):H513-20.

    29.  Richelsen B, Sorensen NS. Alpha 2- and beta-adrenergic receptor binding and action in gluteal adipocytes from patients with hypothyroidism and hyperthyroidism. Metabolism. 1987 Nov;36(11):1031-9.

    30.  Wang JL, Chinookoswong N, Yin S, Shi ZQ. Calorigenic actions of leptin are additive to, but not dependent on, those of thyroid hormones. Am J Physiol Endocrinol Metab. 2000 Dec;279(6):E1278-85.

    31.  Seidel A, Heldmaier G. Thyroid hormones affect the physiological availability of nonshivering thermogenesis. Pflugers Arch. 1982 May;393(3):283-5.

    32.  Jones NL, Heigenhauser GJ, Kuksis A, Matsos CG, Sutton JR, Toews CJ. Fat metabolism in heavy exercise. Clin Sci (Lond). 1980 Dec;59(6):469-78.

    33.  Romijn JA, Coyle EF, Sidossis LS, Zhang XJ, Wolfe RR. Relationship between fatty acid delivery and fatty acid oxidation during strenuous exercise. J Appl Physiol. 1995 Dec;79(6):1939-45.

    34.  Romijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, Wolfe RR. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol Endocrinol Metab. 1993;265:E380-E391.

    35.  Martin WH 3rd, Dalsky GP, Hurley BF, Matthews DE, Bier DM, Hagberg JM, Rogers MA, King DS, Holloszy JO.  Effect of endurance training on plasma free fatty acid turnover and oxidation during exercise. Am J Physiol. 1993;265:E708–14.

    36.  Elayan IM, Winder WW. Effect of glucose infusion on muscle malonyl-CoA during exercise. J Appl Physiol. 1991 Apr;70(4):1495-9.

    37.  Saddik M, Gamble J, Witters LA, Lopaschuk GD. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem. 1993 Dec 5;268(34):25836-45.

    38.  McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest. 1977 Jul;60(1):265-70.

    39.  Robinson IN, Zammit VA. Sensitivity of carnitine acyltransferase I to malonly-CoA inhibition in isolated rat liver mitochondria is quantitatively related to hepatic malonyl-CoA concentration in vivo. Biochem J. 1982 Jul 15;206(1):177-9.

    40.  McGarry JD, Mills SE, Long CS, Foster DW. Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. Biochem J. 1983 Jul 15;214(1):21-8.

    41.  Sidossis LS, Gastaldelli A, Klein S, Wolfe RR. Regulation of plasma fatty acid oxidation during low- and high-intensity exercise. Am J Physiol. 1997;272:E1065–70.

    42.  Mertens DJ, Rhind S, Berkhoff F, Dugmore D, Shek PN, Shephard RJ. Nutritional, immunologic and psychological responses to a 7250 km run. J Sports Med Phys Fitness. 1996 Jun;36(2):132-8.

    43.  Wesche MF, Wiersinga WM. Relation between lean body mass and thyroid volume in competition rowers before and during intensive physical training. Horm Metab Res. 2001 Jul;33(7):423-7.

    44.  Eliakim A, Brasel JA, Mohan S, Barstow TJ, Berman N, Cooper DM. Physical fitness, endurance training, and the growth hormone-insulin-like growth factor I system in adolescent females. J Clin Endocrinol Metab. 1996 Nov;81(11):3986-92.

    45.  Bisschop PH, Sauerwein HP, Endert E, Romijn JA. Isocaloric carbohydrate deprivation induces protein catabolism despite a low T3-syndrome in healthy men. Clin Endocrinol (Oxf). 2001 Jan;54(1):75-80.

    46.  Essig DA, Alderson NL, Ferguson MA, Bartoli WP, Durstine JL. Delayed effects of exercise on the plasma leptin concentration. Metabolism. 2000 Mar;49(3):395-9.

    47.  Kanaley JA, Weltman JY, Pieper KS, Weltman A, Hartman ML. Cortisol and growth hormone responses to exercise at different times of day. J Clin Endocrinol Metab. 2001 Jun;86(6):2881-9.

    48.  Duclos M, Gouarne C, Bonnemaison D. Acute and chronic effects of exercise on tissue sensitivity to glucocorticoids. J Appl Physiol. 2003 Mar;94(3):869-75.

    49.  Duclos M, Corcuff JB, Pehourcq F, Tabarin A. Decreased pituitary sensitivity to glucocorticoids in endurance-trained men. Eur J Endocrinol. 2001 Apr;144(4):363-8.

    50.  Heitkamp HC, Schulz H, Rocker K, Dickhuth HH. Endurance training in females: changes in beta-endorphin and ACTH. Int J Sports Med. 1998 May;19(4):260-4.

    51.  Duclos M, Corcuff JB, Arsac L, Moreau-Gaudry F, Rashedi M, Roger P, Tabarin A, Manier G. Corticotroph axis sensitivity after exercise in endurance-trained athletes. Clin Endocrinol (Oxf). 1998 Apr;48(4):493-501.

    52.  Tyndall GL, Kobe RW, Houmard JA. Cortisol, testosterone, and insulin action during intense swimming training in humans. Eur J Appl Physiol Occup Physiol. 1996;73(1-2):61-5.

    53.  Vasankari TJ, Kujala UM, Heinonen OJ, Huhtaniemi IT. Effects of endurance training on hormonal responses to prolonged physical exercise in males. Acta Endocrinol (Copenh). 1993 Aug;129(2):109-13.

    54.  Hoogeveen AR, Zonderland ML. Relationships between testosterone, cortisol and performance in professional cyclists. Int J Sports Med. 1996 Aug;17(6):423-8.

    55.  Seidman DS, Dolev E, Deuster PA, Burstein R, Arnon R, Epstein Y. Androgenic response to long-term physical training in male subjects. Int J Sports Med. 1990 Dec;11(6):421-4.

    56.  Duclos, M, Corcuff JB, Rashedi M, Fougere V, and Manier G. Trained versus untrained: different hypothalamo-pituitary adrenal axis responses to exercise recovery. Eur J Appl Physiol 75: 343-350, 1997.

    57.  Ma K, Mallidis C, Bhasin S, Mahabadi V, Artaza J, Gonzalez-Cadavid N, Arias J, Salehian B. Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression. Am J Physiol Endocrinol Metab. 2003 Aug;285(2):E363-71.

    58.  Cvijetić S, Grazio S, Gomzi M, Krapac L, Nemcić T, Uremović M, Bobić J. Muscle strength and bone density in patients with different rheumatic conditions: cross-sectional study. Croat Med J. 2011 Apr 15;52(2):164-70.

    59.  Dixon WG, Lunt M, Pye SR, Reeve J, Felsenberg D, Silman AJ, O’Neill TW; European Prospective Osteoporosis Study Group. Low grip strength is associated with bone mineral density and vertebral fracture in women. Rheumatology (Oxford). 2005 May;44(5):642-6.

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    Common Paths to a Low Metabolism

    March 28th, 2014

    Also see:
    Common Paths to a High MetabolismCollection of FPS Charts
    Collection of Ray Peat Quote Blogs by FPS
    Master List – Ray Peat, PhD Interviews
    Components of Daily Energy Expenditure
    Body Temperature, Metabolism, and Obesity

    This chart indicates commons ways in which cell metabolism is suppressed. More than one factor may be acting at once. Commonalities among the factors are lean tissue loss, thyroid suppression, blood sugar dysregulation, malnutrition, steroid hormone imbalance, and frequent activation of systems used to prolong life during actual starvation.

    fps metabolism chart fps


    The Glucose Song

    March 28th, 2014

    Also see:
    Comparison: Carbon Dioxide v. Lactic Acid
    Cellular Energy Production – Aerobic Respiration – The Krebs Cycle
    Carbon Dioxide Basics
    Carbon Dioxide as an Antioxidant
    Comparison: Oxidative Metabolism v. Glycolytic Metabolic
    Promoters of Efficient v. Inefficient Metabolism
    Trauma & Resuscitation: Toxicity of Lactated Ringer’s Solution
    Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide
    Low CO2 in Hypothyroidism
    Protective Altitude
    Protect the Mitochondria
    Lactate Paradox: High Altitude and Exercise
    Altitude Improves T3 Levels
    Protective Carbon Dioxide, Exercise, and Performance
    Synergistic Effect of Creatine and Baking Soda on Performance
    Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
    Mitochondria & Mortality
    Altitude and Mortality

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