It’s about five years since I started actively reading health literature. During these years, I’ve read dozens of health books, thousands of scientific articles and I’ve followed more than 200 different health blogs to gather as many good ideas as possible.
There have been many interesting approaches to optimal health, but it has always been difficult to understand which opinion is the ?right? one. Some of the common?questions include:
– Should we avoid saturated fats, or polyunsaturated fats, or omega-6, or omega-3 fats? (William Lands vs. Chris Masterjohn vs. Ray Peat vs. Brian Peskin vs. Dariush Mozaffarian vs. Caldwell Esselstyn)
– Is sugar healthy or bad? Can starch be healthy? (Ray Peat vs. low carb community vs. Paul Jaminet)
– Is animal protein a good or bad thing (T. Colin Campbell & Vegan community vs. Denise Minger & Loren Cordain & Paleo community)
At first it felt like it was very difficult to trust anybody’s point of view on these issues, because there always seemed to be some contradictory evidence or “paradoxes.”
However, at some point, I started focusing mostly on the possible mechanisms of chronic disease in general?and finally found some powerful ideas that seemed to explain some of these important questions, and the paradoxes as well.
2. Metabolic Rate, Health and Red Light
One of my first important findings was the Broda Barnes? idea that insufficient thyroid function is a very important cause of many kinds of ailments such as heart disease, depression, fibromyalgia, migraine, menstrual problems, and skin diseases. Many 180DegreeHealth ideas have been heavily influenced by Barnes? work.
In 1976, Barnes wrote that 40% of the U.S. population suffered from low metabolic rate, but he didn’t really speculate about the possible mechanisms causing this problem. However, I noticed that biologist Ray Peat had been thinking of these issues for decades.
In some of his articles, Peat pointed out that red light has important metabolic effects, and when I started investigating the issue, I found out that red light and near-infrared light have been beneficially used for almost all kinds of diseases – and they have very important pro-metabolic effects. In some cases, it seems that near-infrared light in the form of a ?low level laser therapy? could even cure chronic diseases such as clinical hypothyroidism.
The biological effects of red light seemed to explain at least a part of the ?low metabolism? epidemic, but there were also alternative explanations I wanted to investigate.
?3. Diet, Endotoxin and Inflammation
Many studies showed that ?endotoxin? and inflammation could cause disturbations of thyroid hormone metabolism. When I looked more closely at the research, many of the dietary “paradoxes”?finally ‘started to make a lot of sense.
When you eat an unbalanced diet high in fat/sugar/alcohol, you get bacterial stuff called ?endotoxin? into your bloodstream.
Endotoxin is not very harmful in itself, but it can activate your immune system via a toll-like receptor 4 (TLR4) which is a very important factor behind metabolic syndrome and other chronic diseases.
Many animal studies have shown that inappropriate amounts of junk food increase endotoxin and lead to abdominal obesity and other problems such as high blood pressure and impaired thyroid hormone metabolism. Studies have also shown that you get the same health problems from a sole endotoxin injection, without the junk food.
It seems that the fat/sugar/alcohol we are eating is actually not so harmful. The harm doesn’t come from these macronutrients. It comes from the diet-induced increase in the blood levels of endotoxin and the subsequent immune reaction. There are actually many studies showing that if you reduce endotoxin levels or reduce inflammation, you make?rats very?resistant to diet-induced obesity and other problems.[2-15]
More on this subject has been written on-site?HERE by Andrew Kim.
4. Glycine: The ?Miracle Nutrient?
At some point, I found some interesting research articles about glycine which is a ?non-essential? amino acid.
There were papers showing that dietary glycine gives a strong protection from endotoxin, and also protects the?liver from many kinds of poisons.
But when I looked further, I also found more than two hundred glycine articles showing that this nutrient also protected animals from diabetes, cancer, methionine, ischemia, hemorrhagic shock, hypercholesterolemia, lead and cadmium toxicity, dental caries, gastric ulcers, birth defects, and several other harmful things. In one study, it also significantly increased the lifespan of rats.
But those effects weren’t even the most interesting ones. I got very excited when I saw the astonishing findings of one Mexican research group.
This research group did something quite nasty to their rats. They added 30% sucrose to their water for 20 weeks. Consequently, the rats got a huge amount of calories from their drinking water and thus their food intake decreased by more than fifty percent. That equals a huge decrease in protein, mineral, and vitamin intake as well.
The rats developed full-blown metabolic syndrome in 20 weeks. But then after 20 weeks the researchers also added 1% glycine to the drinking water. In 4 weeks, the sugar-fed rats became almost as healthy as the control group. With glycine, the rats? blood pressure, fat cells, blood markers and many other things quickly became normalized despite the continued sugar feeding and low nutrient intake.
This result wouldn’t sound even believable to me, if there weren’t a couple of other reports showing similar effects. For example, one study showed that a high-glycine protein source (scallop) prevented the harmful effects of a high-fat, high-sugar diet while other protein sources led to a very significant weight gain:
“In conclusion, intake of scallop muscle as the sole dietary protein source completely prevented high-fat, high-sucrose-induced body mass gain and fat accretion without affecting lean body mass. Furthermore, scallop feeding improved plasma lipid profile in C57BL/6J mice compared to mice fed diets with protein from chicken, cod, or crab. Correlation analyses revealed strong, highly significant inverse correlations between intake of taurine and glycine and body fat mass, as well as strong, highly significant correlations between glycine and especially taurine intake and improved plasma lipid profiles.”[17-20]
These protective effects of glycine seem to be related to the fact that glycine decreases inflammation by hyperpolarizing immune cells via ?glycine-gated chloride channels,? preventing an exaggerated, harmful immune response to endotoxin and other stimuli. I have written about this in my own blog.
?5. An anti-inflammatory diet
I mostly agree with Matt’s ideas about a healthy diet (outlined in his books such as Diet Recovery 2 or Eat for Heat), but I would personally emphasize the importance of nutrients that protect us from endotoxin and the subsequent immune reaction.
While glycine seems to be the most promising anti-inflammatory nutrient, other nutrients such as antioxidants, fiber, probiotics, carnosine, short-chain fatty acids, zinc and vitamin K1/K2 have been shown to have some similar protective effects. Histidine seems to be an especially healthy nutrient according to a recent double-blind supplementation trial with very impressive results.[21-47]
I suspect that saturated fat is the healthiest type of fat, but I also think that it’s healthy only in the context of an anti-inflammatory diet that includes antioxidants, fiber, or glycine. Without the antioxidants, fiber, or glycine, saturated fat might increase endotoxin and inflammation, and cause health problems.[23,48]
And similarly, the effects of sugar also appear to be very context-dependent. The research I’ve seen suggests that sugar is safe when the diet is high in antioxidants or glycine. Honey is healthier than the sugars it contains.
When we are thinking about the health effects of a single nutrient, I think the context matters a lot.
And this logic applies not only to fat and sugar, but also to protein. Denise Minger has explained that animal protein or methionine can be harmful but mostly on a glycine-deficient diet.
As Ray Peat said, “Context is everything.”
In this article, I’m mostly just scratching the surface of the topic of chronic diseases and metabolic syndrome.
What I’m trying to say, is that most health problems seem to be largely associated with inflammation and low thyroid function. These are the health markers that we should possibly prioritize over others.
When we try to prevent heart disease, we most often focus on only cholesterol levels, ignoring that thyroid function might be much more important. Same with fibromyalgia, in which the focus should probably be on energy metabolism.
When we try to prevent diabetes, obesity or liver cirrhosis, we most often focus on blood sugar regulation or sugar/fat intake, ignoring the role of endotoxin and inflammatory processes, which are the main factors behind those diseases.
Some food for thought.
For the interested ones, here are the slides of my glycine presentation:
Vladimir Heiskanen of Finland has been researching and writing about health for several years. Currently a chemistry student at the University of Helsinki and a blogger since 2010, he has a keen interest in human biology, and has studied scores of books, reports and cutting-edge health websites, especially the work of Chris Masterjohn, Paul Jaminet, and Matt Stone. You can read all of his fascinating articles published at 180D HERE, and his own blog HERE.
Valtsu’s – Health Benefits of Glycine
Valtsu’s – The Therapeutic Effects of Red and Near-Infrared Light (long version)
Valtsu’s – Thyroid Hormones: The Ultimate Weapon Against Heart Disease?
Valtsu’s – Fibromyalgia (a draft)
Syontix – PUFAs, Leaky Gut, Endotoxemia, And The Liver
 This has been investigated by a researcher Danilo B. H?fling, in a few studies.
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 Iran J Pharm Res. 2013 Fall;12(4):929-36. Probiotic yogurt Affects Pro- and Anti-inflammatory Factors in Patients with Inflammatory Bowel Disease. Shadnoush M, Shaker Hosseini R, Mehrabi Y, Delpisheh A, Alipoor E, Faghfoori Z, Mohammadpour N, Zaringhalam Moghadam J.
 Biochem Biophys Res Commun. 2013 Feb 8;431(2):258-63. Lactobacillus rhamnosus GG improves insulin sensitivity and reduces adiposity in high-fat diet-fed mice through enhancement of adiponectin production. Kim SW, Park KY, Kim B, Kim E, Hyun CK.
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 Am J Pathol. 2011 Dec;179(6):2866-75. Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxia-inducible factor, promotes intestinal integrity and ameliorates alcohol-induced liver injury. Wang Y1, Kirpich I, Liu Y, Ma Z, Barve S, McClain CJ, Feng W.
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 World J Gastroenterol. 2013 Jan 14;19(2):274-83. Dual probiotic strains suppress high fructose-induced metabolic syndrome. Park DY, Ahn YT, Huh CS, McGregor RA, Choi MS.
 Diabetologia. 2013 May;56(5):985-94. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. Feng RN, Niu YC, Sun XW, Li Q, Zhao C, Wang C, Guo FC, Sun CH, Li Y.
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Extra references (lots of very useful literature)
[extra] Bol Med Hosp Infant Mex Vol. 67, March-April 2010 Obesity as an inflammatory process. Blancas-Flores G, Almanza-P?rez JC, L?pez-Roa RI, Alarc?n-Aguilar FJ, Garc?a-Macedo R, Cruz M.
[extra] Diabetes Care. 2011 Aug;34(8):1809-15. doi: 10.2337/dc10-2197. Epub 2011 Jun 2. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Lassenius MI, Pietil?inen KH, Kaartinen K, Pussinen PJ, Syrj?nen J, Forsblom C, P?rsti I, Rissanen A, Kaprio J, Mustonen J, Groop PH, Lehto M; FinnDiane Study Group.
[extra] Dig Dis Sci. 2012 Jul;57(7):1932-41. doi: 10.1007/s10620-012-2112-9. Epub 2012 Mar 17. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Volynets V, K?per MA, Strahl S, Maier IB, Spruss A, Wagnerberger S, K?nigsrainer A, Bischoff SC, Bergheim I. “Despite no differences in the prevalence of bacterial overgrowth and in the orocecal transit time, intestinal permeability, alcohol, and endotoxin levels in plasma were significantly higher in patients with NAFLD than in controls.”
[extra] Surgery. 2012 Apr;151(4):587-93. doi: 10.1016/j.surg.2011.09.038. Epub 2011 Nov 16. Reduction in endotoxemia, oxidative and inflammatory stress, and insulin resistance after Roux-en-Y gastric bypass surgery in patients with morbid obesity and type 2 diabetes mellitus. Monte SV, Caruana JA, Ghanim H, Sia CL, Korzeniewski K, Schentag JJ, Dandona P. “LPS, NF-?B DNA binding, TLR-4, TLR-2, and CD14 expression, CRP, MMP-9, and MCP-1 decreased significantly after RYGB. The mechanism underlying resolution of insulin resistance and T2DM after RYGB may be attributable, at least in part, to the reduction of endotoxemia and associated proinflammatory mediators.”
[extra] Gastroenterology. 2012 May;142(5):1100-1101.e2. doi: 10.1053/j.gastro.2012.01.034. Epub 2012 Feb 8. A high-fat diet is associated with endotoxemia that originates from the gut. Pendyala S1, Walker JM, Holt PR. “Placing 8 healthy subjects on a Western-style diet for 1 month induced a 71% increase in plasma levels of endotoxin activity (endotoxemia), whereas a prudent-style diet reduced levels by 31%. The Western-style diet might, therefore, contribute to endotoxemia by causing changes in gastrointestinal barrier function or the composition of the microbiota.”
[extra] Diabetes Care. 2009 Dec;32(12):2281-7. doi: 10.2337/dc09-0979. Epub 2009 Sep 15. Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Ghanim H1, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM, Dandona P. “HFHC meal intake induced an increase in plasma LPS concentration and the expression of SOCS-3, TLR2, and TLR4 protein, reactive oxygen species generation, and nuclear factor-kappaB binding activity (P < 0.05 for all). These increases were totally absent after the AHA meal rich in fiber and fruit.”
[extra] Am J Clin Nutr. 2007 Nov;86(5):1286-92. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Erridge C, Attina T, Spickett CM, Webb DJ. “Baseline endotoxin concentrations were 8.2 pg/mL (interquartile range: 3.4-13.5 pg/mL) but increased significantly (P < 0.05) by approximately 50% after a high-fat meal or after a high-fat meal with cigarettes but not after no meal or cigarettes alone. These results were validated by the observations that a high-fat meal with or without cigarettes, but not no meal or smoking, also significantly (P < 0.05) reduced plasma endotoxin neutralization capacity, which is an indirect measure of endotoxin exposure”
[extra] Diabetes Care. 2010 May;33(5):991-7. doi: 10.2337/dc09-1630. Epub 2010 Jan 12. Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Deopurkar R, Ghanim H, Friedman J, Abuaysheh S, Sia CL, Mohanty P, Viswanathan P, Chaudhuri A, Dandona P. “Although both glucose and cream induce NF-kappaB binding and an increase in the expression of SOCS3, TNF-alpha, and IL-1beta in MNCs, only cream caused an increase in LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did not induce a change in any of these indexes. These changes are relevant to the pathogenesis of atherosclerosis and insulin resistance.”
[extra] Diabetes. 2012 Jun;61(6):1455-62. doi: 10.2337/db11-0390. Epub 2012 Apr 20. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Milanski M, Arruda AP, Coope A, Ignacio-Souza LM, Nunez CE, Roman EA, Romanatto T, Pascoal LB, Caricilli AM, Torsoni MA, Prada PO, Saad MJ, Velloso LA. “Obese rodents were treated by intracerebroventricular injections, with immunoneutralizing antibodies against Toll-like receptor (TLR)4 or tumor necrosis factor (TNF)?, and insulin signal transduction, hepatic steatosis, and gluconeogenesis were evaluated. The inhibition of either TLR4 or TNF? reduced hypothalamic inflammation, which was accompanied by the reduction of hypothalamic resistance to leptin and improved insulin signal transduction in the liver. This was accompanied by reduced liver steatosis and reduced hepatic expression of markers of steatosis. Furthermore, the inhibition of hypothalamic inflammation restored defective liver glucose production”
[extra] PLoS One. 2014 May 14;9(5):e96864. doi: 10.1371/journal.pone.0096864. eCollection 2014. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. Bala S, Marcos M, Gattu A, Catalano D, Szabo G.
[extra] Am J Gastroenterol. 2002 Sep;97(9):2364-70. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Bauer TM, Schwacha H, Steinbr?ckner B, Brinkmann FE, Ditzen AK, Aponte JJ, Pelz K, Berger D, Kist M, Blum HE.
[extra] Diabetes Care. 2011 Feb;34(2):392-7. doi: 10.2337/dc10-1676. Endotoxemia is associated with an increased risk of incident diabetes. Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V.
[extra] Nutr Metab (Lond). 2013 Jan 10;10(1):6. Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia. Mani V, Hollis JH, Gabler NK.
[extra] Exp Physiol. 2014 Jun 27. [Epub ahead of print] Fructose supplementation worsens the deleterious effects of short term high fat feeding on hepatic steatosis and lipid metabolism in adult rats. Crescenzo R, Bianco F, Coppola P, Mazzoli A, Tussellino M, Carotenuto R, Liverini G, Iossa S.
[extra] Alcohol Clin Exp Res. 2012 May;36(5):835-46. doi: 10.1111/j.1530-0277.2011.01673.x. Epub 2011 Dec 7. The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Kirpich IA, Feng W, Wang Y, Liu Y, Barker DF, Barve SS, McClain CJ. “Compared with control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p < 0.05) increased in USF + EtOH, but not in SF + EtOH group.”
[extra] J Neurochem. 2007 May;101(3):729-36. Epub 2007 Jan 24. Neuroprotective actions of a histidine analogue in models of ischemic stroke. Tang SC, Arumugam TV, Cutler RG, Jo DG, Magnus T, Chan SL, Mughal MR, Telljohann RS, Nassar M, Ouyang X, Calderan A, Ruzza P, Guiotto A, Mattson MP. “We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE)[…]”
[extra] Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1162-70. doi: 10.1161/ATVBAHA.112.300572. Epub 2013 Apr 4. Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Barski OA, Xie Z, Baba SP, Sithu SD, Agarwal A, Cai J, Bhatnagar A, Srivastava S.
[extra] Br J Pharmacol. 2012 Jun;166(4):1344-56. doi: 10.1111/j.1476-5381.2012.01834.x. D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Menini S, Iacobini C, Ricci C, Scipioni A, Blasetti Fantauzzi C, Giaccari A, Salomone E, Canevotti R, Lapolla A, Orioli M, Aldini G, Pugliese G.
[extra] Gastroenterology. 2009 Feb;136(2):564-74.e2. doi: 10.1053/j.gastro.2008.09.062. Epub 2008 Oct 7. Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Andou A, Hisamatsu T, Okamoto S, Chinen H, Kamada N, Kobayashi T, Hashimoto M, Okutsu T, Shimbo K, Takeda T, Matsumoto H, Sato A, Ohtsu H, Suzuki M, Hibi T.
[extra] Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1095-104. Epub 2007 Jan 12. Protective effect of orally administered carnosine on bleomycin-induced lung injury. Cuzzocrea S, Genovese T, Failla M, Vecchio G, Fruciano M, Mazzon E, Di Paola R, Mui? C, La Rosa C, Crimi N, Rizzarelli E, Vancheri C.
[extra] Diabetes. 2013 Jul;62(7):2266-77. doi: 10.2337/db12-1701. Epub 2013 Mar 8. Histidine augments the suppression of hepatic glucose production by central insulin action. Kimura K1, Nakamura Y, Inaba Y, Matsumoto M, Kido Y, Asahara S, Matsuda T, Watanabe H, Maeda A, Inagaki F, Mukai C, Takeda K, Akira S, Ota T, Nakabayashi H, Kaneko S, Kasuga M, Inoue H.
[extra] Hum Exp Toxicol. 2010 Aug;29(8):659-65. The effect of carnosine pretreatment on oxidative stress and hepatotoxicity in binge ethanol administered rats. Artun BC, K’sk?-Kiraz Z, G’ll?o?lu M, Cevikba? U, Ko?ak-Toker N, Uysal M. “In conclusion, carnosine prevented the increases in serum transaminase activities and lipid peroxides in liver of ethanol-treated rats, without any change on steatosis in liver.”
[extra] Neurosci Lett. 2012 Feb 21;510(1):1-5. Effects of L-carnosine on splenic sympathetic nerve activity and tumor proliferation. Horii Y, Shen J, Fujisaki Y, Yoshida K, Nagai K. “The tumor volumes of the control mice given water gradually and markedly increased and reached a value of 869.8 ? 132.9 mm3 on day 22 after implantation (Fig. 3b). The tumor volumes of the l-carnosine group also increased; however, the increase was less than that of the control group, reaching a value of 407.8 ? 121.7 mm3 (46.9% of the tumor volume of the control group) on day 22.”
[extra] Nutr Clin Pract. 2013 Oct;28(5):609-16. doi: 10.1177/0884533613493333. Epub 2013 Jul 8. Effects of L-carnosine and its zinc complex (Polaprezinc) on pressure ulcer healing. Sakae K, Agata T, Kamide R, Yanagisawa H. “After 4 weeks, the rate of pressure ulcer healing, assessed by the mean weekly improvement in PUSH score, was significantly greater in the CAR (1.6 ? 0.2, P = .02) and PLZ groups (1.8 ? 0.2, P = .009) than in the control group (0.8 ? 0.2).”
[extra] Intern Med. 2011;50(15):1569-74. Inflammatory cytokines, adiponectin, insulin resistance and metabolic control after periodontal intervention in patients with type 2 diabetes and chronic periodontitis. Sun WL, Chen LL, Zhang SZ, Wu YM, Ren YZ, Qin GM.
[extra] J Clin Periodontol. 2010 Jan;37(1):53-8. Effect of periodontal treatment on metabolic control, systemic inflammation and cytokines in patients with type 2 diabetes. Correa FO1, Gon?alves D, Figueredo CM, Bastos AS, Gustafsson A, Orrico SR.
[extra] FEBS Letters Volume 581, Issue 3, 6 February 2007, Pages 349?354: Augmentation of 11?-hydroxysteroid dehydrogenase type 1 in LPS-activated J774.1 macrophages ? Role of 11?-HSD1 in pro-inflammatory properties in macrophages Takako Ishii, Hiroaki Masuzaki, Tomohiro Tanaka, Naoki Arai, Shintaro Yasue, Nozomi Kobayashi, Tsutomu Tomita, Michio Noguchi, Junji Fujikura, Ken Ebihara, Kiminori Hosoda, Kazuwa Nakao
[extra] J Neurochem. 2012 Mar;120(6):1060-71. doi: 10.1111/j.1471-4159.2012.07660.x. Epub 2012 Feb 6. Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. Gupta S, Knight AG, Gupta S, Keller JN, Bruce-Keller AJ. “Data show that the saturated fatty acid palmitic acid, as well as lauric acid and stearic acid, trigger the release of TNF? and IL-6 from astrocytes. Unsaturated fatty acids were unable to induce cytokine release from cultured astrocytes. Furthermore, the effects of palmitic acid on cytokine release require Toll-like receptor 4 rather than CD36 or Toll-like receptor 2, and do not depend on palmitic acid metabolism to palmitoyl-CoA. […] Finally, data show that the essential ?-3 fatty acid docosahexaenoic acid acts in a dose-dependent manner to prevent the actions of palmitic acid on inflammatory signaling in astrocytes. Collectively, these data demonstrate the ability of saturated fatty acids to induce astrocyte inflammation in vitro.“
[extra] J Neurosci. 2009 Jan 14;29(2):359-70. doi: 10.1523/JNEUROSCI.2760-08.2009. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DM, Anhe G, Amaral ME, Takahashi HK, Curi R, Oliveira HC, Carvalheira JB, Bordin S, Saad MJ, Velloso LA. “According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity”
[extra] Endocrinology. 2011 Apr;152(4):1314-26. doi: 10.1210/en.2010-0659. Epub 2011 Jan 25. Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Arruda AP, Milanski M, Coope A, Torsoni AS, Ropelle E, Carvalho DP, Carvalheira JB, Velloso LA. “In Wistar rats, hypothalamic TNF? blunts the anorexigenic effect of leptin, which is accompanied by reduced leptin signaling and increased expression of suppressor of cytokine signaling 3. In addition, hypothalamic TNF? reduces O(2) consumption and the expression of thermogenic proteins in brown adipose tissue and skeletal muscle. Furthermore, hypothalamic inflammation increases base-line plasma insulin and insulin secretion by isolated pancreatic islets, which is accompanied by an impaired insulin signal transduction in liver and skeletal muscle. Hypothalamic inflammation induced by stearic acid also reduces O(2) consumption and blunts peripheral insulin signal transduction. The use of intracerebroventricular infliximab restores O(2) consumption in obese rats, whereas TNF receptor 1-knockout mice are protected from diet-induced reduced thermogenesis and defective insulin signal transduction. Thus, low-grade inflammation of the hypothalamus is sufficient to induce changes in a number of parameters commonly impaired in obesity and DM2, and TNF? is an important mediator of this process.”
[extra] J Biol Chem. 2009 Dec 25;284(52):36213-22. doi: 10.1074/jbc.M109.030874. Epub 2009 Oct 26. Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. Romanatto T1, Roman EA, Arruda AP, Denis RG, Solon C, Milanski M, Moraes JC, Bonfleur ML, Degasperi GR, Picardi PK, Hirabara S, Boschero AC, Curi R, Velloso LA.
[extra] Br J Nutr. 2012 Jan;107(2):229-41. doi: 10.1017/S0007114511002868. Epub 2011 Jun 29. Saturated fatty acids activate microglia via Toll-like receptor 4/NF-?B signalling. Wang Z, Liu D, Wang F, Liu S, Zhao S, Ling EA, Hao A.
[extra] J Biol Chem. 2001 May 18;276(20):16683-9. Epub 2001 Mar 2. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. Lee JY, Sohn KH, Rhee SH, Hwang D.
[extra] vDiabetologia. 2007 Jun;50(6):1267-76. Epub 2007 Apr 11. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC.
[extra] Obesity (Silver Spring). 2008 Jun;16(6):1248-55. doi: 10.1038/oby.2008.210. Epub 2008 Apr 10. Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Davis JE1, Gabler NK, Walker-Daniels J, Spurlock ME.
[extra] J Nutr Biochem. 2011 Feb;22(2):136-41. doi: 10.1016/j.jnutbio.2009.12.008. Absence of Tlr2 protects against high-fat diet-induced inflammation and results in greater insulin-stimulated glucose transport in cultured adipocytes. Davis JE, Braucher DR, Walker-Daniels J, Spurlock ME.
[extra] Cell Metab. 2009 Oct;10(4):249-59. doi: 10.1016/j.cmet.2009.08.013. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Kleinridders A, Schenten D, K?nner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, Br?ning JC.
[extra] Circ Res. 2007 Jun 8;100(11):1589-96. Epub 2007 May 3. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Kim F1, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW.
[extra] FASEB J. 2012 Aug;26(8):3493-502. doi: 10.1096/fj.12-208868. Epub 2012 May 16. Timed high-fat diet resets circadian metabolism and prevents obesity. Sherman H, Genzer Y, Cohen R, Chapnik N, Madar Z, Froy O. “Although timed HF-diet-fed mice consumed the same amount of calories as ad libitum low-fat diet-fed mice, they showed 12% reduced body weight, 21% reduced cholesterol levels, and 1.4-fold increased insulin sensitivity. Compared with the HF diet ad libitum, the timed HF diet led to 18% lower body weight, 30% decreased cholesterol levels, 10% reduced TNF-? levels, and 3.7-fold improved insulin sensitivity. Timed HF-diet-fed mice exhibited a better satiated and less stressed phenotype of 25% lower ghrelin and 53% lower corticosterone levels compared with mice fed the timed low-fat diet.”
[extra] FASEB J. 2010 Dec;24(12):4948-59. doi: 10.1096/fj.10-164921. Epub 2010 Aug 19. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. Rabot S, Membrez M, Bruneau A, G?rard P, Harach T, Moser M, Raymond F, Mansourian R, Chou CJ.
[extra] PLoS One. 2010 Aug 16;5(8):e12191. doi: 10.1371/journal.pone.0012191. High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. Ding S, Chi MM, Scull BP, Rigby R, Schwerbrock NM, Magness S, Jobin C, Lund PK. “Bacteria and HF diet interact to promote proinflammatory changes in the small intestine, which precede weight gain and obesity and show strong and significant associations with progression of obesity and development of insulin resistance. To our knowledge, this is the first evidence that intestinal inflammation is an early consequence of HF diet which may contribute to obesity and associated insulin resistance. Interventions which limit intestinal inflammation induced by HF diet and bacteria may protect against obesity and insulin resistance.”
[extra] Atherosclerosis. 2011 May;216(1):1-6. doi: 10.1016/j.atherosclerosis.2011.02.043. Epub 2011 Feb 26. Diet, commensals and the intestine as sources of pathogen-associated molecular patterns in atherosclerosis, type 2 diabetes and non-alcoholic fatty liver disease. Erridge C. “This review summarises the evidence supporting the proposal that ‘pathogen-associated molecular patterns’ (PAMPs) derived from dietary and commensal sources may contribute to the chronic inflammatory processes that underpin the development of these diseases via stimulation of TLR2 and TLR4.”
[extra] Metabolism. 2006 Sep;55(9):1177-85. Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Aljada A, Friedman J, Ghanim H, Mohanty P, Hofmeyer D, Chaudhuri A, Dandona P.
[extra] Diabetologia. 2007 Feb;50(2):278-85. Epub 2006 Dec 16. Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects. Ghanim H, Aljada A, Daoud N, Deopurkar R, Chaudhuri A, Dandona P. “We conclude that in obesity the MNC is characterised by reduced p-INSR-beta and increased inflammatory mediators including IKBKB, PRKCB2 and SOCS3. The increase in SOCS3 but not IKBKB or PRKCB2 is related inversely to p-INSR-beta and might mediate the inhibition of p-INSR-beta.”
[extra] Gut. 2012 Dec;61(12):1701-7. doi: 10.1136/gutjnl-2011-301689. Epub 2012 Apr 25. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Caesar R1, Reigstad CS, B?ckhed HK, Reinhardt C, Ketonen M, Lund?n G?, Cani PD, B?ckhed F.
[extra] FASEB J. 2008 Jul;22(7):2416-26. doi: 10.1096/fj.07-102723. Epub 2008 Mar 7. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. Membrez M, Blancher F, Jaquet M, Bibiloni R, Cani PD, Burcelin RG, Corthesy I, Mac? K, Chou CJ.
[extra] PLoS One. 2012;7(3):e32967. doi: 10.1371/journal.pone.0032967. Epub 2012 Mar 7. Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats. de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE.
[extra] MBio. 2014 Jun 10;5(3). pii: e01011-14. doi: 10.1128/mBio.01011-14. Saccharomyces boulardii Administration Changes Gut Microbiota and Reduces Hepatic Steatosis, Low-Grade Inflammation, and Fat Mass in Obese and Type 2 Diabetic db/db Mice. Everard A, Matamoros S, Geurts L, Delzenne NM, Cani PD.
[extra] Diabetes Metab Syndr Obes. 2012;5:175-89. doi: 10.2147/DMSO.S33473. Epub 2012 Jul 6. Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity. Spreadbury I.
[extra] Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):84-91. Epub 2006 Nov 2. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y. “These findings suggest that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-kappaB activation.”
[extra] Cell. 2011 Nov 11;147(4):868-80. doi: 10.1016/j.cell.2011.09.051. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC. “These data establish that upon microbial detection, an upstream PRR (CD14) controls the trafficking and signaling functions of a downstream PRR (TLR4).”
[extra] Ann Surg. 2003 Feb;237(2):246-55. Protective effects of medium-chain triglycerides on the liver and gut in rats administered endotoxin. Kono H, Fujii H, Asakawa M, Yamamoto M, Matsuda M, Maki A, Matsumoto Y. “All rats given corn oil died after LPS administration; however, this mortality was prevented by MCT in a dose-dependent manner. Rats given corn oil showed liver injury after LPS administration. In contrast, MCT prevented this pathologic change nearly completely. MCT blunted CD14 expression on the Kupffer cells and TNF-alpha production by isolated Kupffer cells; however, there were no differences in phagocytic index between the two groups. The length of the intestinal epithelium was increased in the MCT group compared to the corn oil group. Further, after LPS administration, increases in gut permeability and injury were prevented by MCT. Importantly, MCT also prevented hepatic energy charge and gut injuries in this condition.”
[extra] Am J Physiol Gastrointest Liver Physiol. 2013 Dec;305(12):G919-32. doi: 10.1152/ajpgi.00226.2013. Epub 2013 Oct 10. Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats. Zhong W, Li Q, Xie G, Sun X, Tan X, Sun X, Jia W, Zhou Z.
[extra] J Gastroenterol. 2013 Aug 17. Toll-like receptor 4 activation in Barrett’s esophagus results in a strong increase in COX-2 expression. Verbeek RE, Siersema PD, Ten Kate FJ, Fluiter K, Souza RF, Vleggaar FP, Bus P, van Baal JW.
[extra] Gastroenterology. 2006 Sep;131(3):862-77. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine. Fukata M, Chen A, Klepper A, Krishnareddy S, Vamadevan AS, Thomas LS, Xu R, Inoue H, Arditi M, Dannenberg AJ, Abreu MT.
[extra] J Leukoc Biol. 2009 Oct;86(4):971-80. doi: 10.1189/jlb.0708396. Epub 2009 Jun 29. TLR4-mediated Cox-2 expression increases intestinal ischemia/reperfusion-induced damage. Moses T, Wagner L, Fleming SD.
[extra] BMC Gastroenterol. 2010 Jul 16;10:82. doi: 10.1186/1471-230X-10-82. The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia. Hernandez Y, Sotolongo J, Breglio K, Conduah D, Chen A, Xu R, Hsu D, Ungaro R, Hayes LA, Pastorini C, Abreu MT, Fukata M.
[extra] Inflamm Bowel Dis. 2011 Jul;17(7):1464-73. Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Fukata M1, Shang L, Santaolalla R, Sotolongo J, Pastorini C, Espa?a C, Ungaro R, Harpaz N, Cooper HS, Elson G, Kosco-Vilbois M, Zaias J, Perez MT, Mayer L, Vamadevan AS, Lira SA, Abreu MT.
[extra] J Immunol. 2009 Feb 15;182(4):2476-84. doi: 10.4049/jimmunol.0802059. Lactate boosts TLR4 signaling and NF-kappaB pathway-mediated gene transcription in macrophages via monocarboxylate transporters and MD-2 up-regulation. Samuvel DJ1, Sundararaj KP, Nareika A, Lopes-Virella MF, Huang Y.
[extra] J Neurosci. 2010 Jun 16;30(24):8285-95. doi: 10.1523/JNEUROSCI.0976-10.2010. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C.
[extra] Front Cell Neurosci. 2014 May 27;8:146. doi: 10.3389/fncel.2014.00146. eCollection 2014. TLR4-mediated brain inflammation halts neurogenesis: impact of hormonal replacement therapy. Mouihate A. “These data strongly suggest that combined 17?-estradiol and progesterone, and not 17?-estradiol alone, rescues neurogenesis from the deleterious effect of brain inflammation likely via the inhibition of the signaling pathways leading to the activation of proinflammatory genes.”
[extra] Wiad Lek. 2013;66(1):3-9. [The role of TLR4 receptor in development of inflammation and carcinogenesis in ulcerative colitis and pharmacotherapy of this disorder]. [Article in Polish] Szumilas D1, Krysiak R, Okopie? B. “The increased expression of TLR4 and the development of the uncontrolled inflammatory response in UC (increased production of COX-2, PGE2, TNFalpha and CCL2) impairs regeneration of the mucosa, resulting in its damage, and may later lead to the development of colon cancer.”
[extra] AAPS J. 2014 Mar;16(2):246-57. doi: 10.1208/s12248-013-9558-3. Epub 2014 Jan 15. Antitumor activity of gemcitabine can be potentiated in pancreatic cancer through modulation of TLR4/NF-?B signaling by 6-shogaol. Zhou L, Qi L, Jiang L, Zhou P, Ma J, Xu X, Li P. “Overall, our results suggest that 6-shogaol can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing of TLR4/NF-?B-mediated inflammatory pathways linked to tumorigenesis.”
[extra] Inflammation. 2014 Apr;37(2):467-77. doi: 10.1007/s10753-013-9760-6. Saturated fatty acids up-regulate COX-2 expression in prostate epithelial cells via toll-like receptor 4/NF-?B signaling. Liu J, Hu S, Cui Y, Sun MK, Xie F, Zhang Q, Jin J.
[extra] Biochem Biophys Res Commun. 2013 Aug 23;438(2):249-56. doi: 10.1016/j.bbrc.2013.07.006. Epub 2013 Jul 11. Differential COX-2 induction by viral and bacterial PAMPs: Consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies. Kirkby NS, Zaiss AK, Wright WR, Jiao J, Chan MV, Warner TD, Herschman HR, Mitchell JA. “LPS induced Cox2 expression in all tissues examined. In contrast, poly(I:C) elicited a milder response, limited to a subset of tissues.”
[extra] J Dent Res. 2009 Jun;88(6):519-23. doi: 10.1177/0022034509338353. Is obesity an oral bacterial disease? Goodson JM, Groppo D, Halem S, Carpino E. “Classification tree analysis of salivary microbiological composition revealed that 98.4% of the overweight women could be identified by the presence of a single bacterial species (Selenomonas noxia) at levels greater than 1.05% of the total salivary bacteria.”
[extra] Aging Cell. 2013 Dec;12(6):1041-9. doi: 10.1111/acel.12133. Epub 2013 Aug 20. The phytochemical, EGCG, extends lifespan by reducing liver and kidney function damage and improving age-associated inflammation and oxidative stress in healthy rats. Niu Y, Na L, Feng R, Gong L, Zhao Y, Li Q, Li Y, Sun C.
[extra] Biochem Biophys Res Commun. 2012 Oct 5;426(4):480-5. doi: 10.1016/j.bbrc.2012.08.096. Epub 2012 Aug 29. Green tea polyphenol epigallocatechin-3-gallate inhibits TLR4 signaling through the 67-kDa laminin receptor on lipopolysaccharide-stimulated dendritic cells. Byun EB, Choi HG, Sung NY, Byun EH.
[extra] J Immunol. 2010 Jul 1;185(1):33-45. doi: 10.4049/jimmunol.0903742. Epub 2010 May 28. TLR4 signaling inhibitory pathway induced by green tea polyphenol epigallocatechin-3-gallate through 67-kDa laminin receptor. Hong Byun E1, Fujimura Y, Yamada K, Tachibana H.
[extra] Mediators Inflamm. 2009;2009:704706. doi: 10.1155/2009/704706. Epub 2010 Feb 16. Oxymatrine downregulates TLR4, TLR2, MyD88, and NF-kappaB and protects rat brains against focal ischemia. Fan H, Li L, Zhang X, Liu Y, Yang C, Yang Y, Yin J. “The excessive inflammatory immune reaction often resides in region of necrosis and ischemic tissue after cerebral infarction and leads to inflammatory injury. The relationship between toll-like receptor-4 (TLR4), toll-like receptor-2 (TLR2), and nonbiological inflammatory injury has been proved [1?3]. It is believed that injured tissue and necrotic cells release endogenous activators (adjuvants). These activators can combine with TLR4 in the cell membrane. […] An excessive inflammatory reaction can also damage target cells and tissue [4, 5]. Reducing the inflammatory injury is therefore regarded to be one of major ways to treat acute cerebral infarction.”
[extra] Stroke. 2013 Jan;44(1):205-12. Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke. Bae ON, Serfozo K, Baek SH, Lee KY, Dorrance A, Rumbeiha W, Fitzgerald SD, Farooq MU, Naravelta B, Bhatt A, Majid A. “In both permanent and transient ischemic models, carnosine treatment exhibited significant cerebroprotection against histological and functional damage, with wide therapeutic and clinically relevant time windows. Carnosine was well tolerated and exhibited no toxicity.”
[extra] Rejuvenation Res. 2008 Feb;11(1):201-14. doi: 10.1089/rej.2007.0608. Dietary supplementation exerts neuroprotective effects in ischemic stroke model. Yasuhara T, Hara K, Maki M, Masuda T, Sanberg CD, Sanberg PR, Bickford PC, Borlongan CV.
[extra] Cardiovasc Res. 2004 Feb 15;61(3):538-47. Modulating Toll-like receptor mediated signaling by (1–>3)-beta-D-glucan rapidly induces cardioprotection. Li C, Ha T, Kelley J, Gao X, Qiu Y, Kao RL, Browder W, Williams DL. “GP treatment reduced infarct size by 47% in rat hearts subjected to reperfusion for 4 h”
[extra] J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4. Epub 2007 Aug 14. Association between hypothyroidism and small intestinal bacterial overgrowth. Lauritano EC, Bilotta AL, Gabrielli M, Scarpellini E, Lupascu A, Laginestra A, Novi M, Sottili S, Serricchio M, Cammarota G, Gasbarrini G, Pontecorvi A, Gasbarrini A.
[extra] Gut. 2007 Feb;56(2):168-75. Epub 2006 Jun 15. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Mahmood A, FitzGerald AJ, Marchbank T, Ntatsaki E, Murray D, Ghosh S, Playford RJ.
[extra] J Clin Biochem Nutr. 2010 May;46(3):234-43. doi: 10.3164/jcbn.09-125. Epub 2010 Apr 10. Polaprezinc Protects Mice against Endotoxin Shock. Ohata S, Moriyama C, Yamashita A, Nishida T, Kusumoto C, Mochida S, Minami Y, Nakada J, Shomori K, Inagaki Y, Ohta Y, Matsura T. “PZ pretreatment inhibited the decrease in the survival rate of mice after LPS injection. PZ inhibited the increases in plasma NO as well as TNF-alpha after LPS. Compatibly, PZ suppressed LPS-induced inducible NO synthase mRNA transcription in the mouse lungs. PZ also improved LPS-induced lung injury.”
[extra] ISME J. 2013 Apr;7(4):880-4. doi: 10.1038/ismej.2012.153. Epub 2012 Dec 13. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. Fei N, Zhao L.
[extra] J Am Coll Cardiol. 1999 Dec;34(7):1975-81. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. Wiedermann CJ1, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, Willeit J. “Median endotoxin concentration amounted to 14.3 pg/ml (range, 6.0 to 209.2 pg/ml). Subjects with levels beyond 50 pg/ml (90th percentile) faced a threefold risk of incident atherosclerosis (odds ratio [95% confidence interval] 2.9 [1.4-6.3]; p < 0.01). The risk associated with high endotoxin was most pronounced in subjects with chronic infections and in current and ex-smokers.”
[extra] Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2227-36. Epub 2004 Oct 7. Potential role of endotoxin as a proinflammatory mediator of atherosclerosis. Stoll LL, Denning GM, Weintraub NL. “In this article, we outline the main elements of the endotoxin signaling receptor complex that initiates proinflammatory signaling (lipopolysaccharide binding protein [LBP], CD14, TLR-4, and MD-2) and discuss how changes in expression of these molecules may affect proatherogenic responses in the vessel wall. We also describe some of the proinflammatory effects of endotoxin that may be relevant to atherosclerosis, and discuss how serum lipoproteins, especially high-density lipoprotein, may modulate endotoxin-induced inflammatory responses. Further, we discuss recent findings suggesting that the lipid-lowering statins may have an additional protective role in blocking at least some of these proinflammatory signaling pathways.”
[extra] Metab Brain Dis. 2014 Mar;29(1):19-36. doi: 10.1007/s11011-013-9435-x. Epub 2013 Sep 10. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Morris G, Maes M. “Increased levels of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-?, and elastase, and increased O&NS may inhibit mitochondrial respiration, decrease the activities of the electron transport chain and mitochondrial membrane potential, increase mitochondrial membrane permeability, interfere with ATP production and cause mitochondrial shutdown. The activated O&NS pathways may additionally lead to damage of mitochondrial DNA and membranes thus decreasing membrane fluidity. Lowered levels of antioxidants, zinc and coenzyme Q10, and ?3 polyunsaturated fatty acids in ME/cfs may further aggravate the activated immuno-inflammatory and O&NS pathways.”
This is extremely fascinating. So most people are probably on a glycine-deficient diet (and most definitely K2-deficient diet)? Also, I get about 10g of glycine per day from gelatin. Do you think it’s worth it to increase my glycine intake even higher?
Yea, I think that many people could possibly benefit from extra glycine. Especially those who have chronic health problems involving inflammation.
I don’t really know what is the optimal daily intake of glycine. I suspect that you get 80% of the benefit from the first 4-8 grams but that just my “educated guess”.
Joel Brind’s supplement has 8 grams of glycine: http://sweetamine.com/
I started taking 3-6 grams of extra glycine daily. And one gram of histidine.
Vladimir,Do you know if there’s anything else besides glycine in Joel Brind’s product to make it effective? Glycine in the U.S. is cheap. So is there some reason to buy his product which is not as cheap as the glycine I can get in a health food store?
It seems that Sweetamine also had proline, taurine and vitamin C.
Taurine might also be beneficial, but I don’t know much about the effects of proline or vitamin C. Probably not as useful as glycine.
I wonder how Sweetamine tastes. I can’t tolerate the taste of pure glycine, so I put my glycine powder into empty “double 00” capsules.
Sweetamine contains glycine, proline, taurine and a little stevia extract. Glycine is the real active ingredient (8 grams per serving). I hardly think there would be any benefit to taking more than 10g/day of supplemental glycine. After all, 8 grams is the equivalent of eating about 16 100g servings of gelatin dessert. Sweetamine is a lot cheaper than that! It is true that you can get plain glycine cheaper on line (not necessarily cheaper at health food stores), although, as Vladimir says, it has a pretty bad aftertaste in pure form. The other ingredients in sweetamine are primarily for taste, and the stick packs make it very convenient. But however you get your extra glycine, it’s important to get it. I think my most important discovery is that much of what is believed to be normal inflammation is not normal at all. Contrary to the prevailing medical and scientific dogma, inflammation is not part of the healing response nor a natural reaction to tissue injury. It is only a natural reaction to the detection of such molecules as bacterial lipopolysaccharides; the generic signature of bacteria. If there is no breach of a barrier, allowing for the influx of bacteria–such as in blunt injuries or sunburn–inflammation is inappropriate, and it does not happen to me anymore, nor anyone who gets enough glycine in their diet. Finally, we are paying attention to and learning about the true role of inflammation–35 years after I studied immunology in graduate school! You can read much more about it on my website and blog http://www.sweetamine.com.
Thanks for your comment, Joel. This part is very fascinating:
“Contrary to the prevailing medical and scientific dogma, inflammation is not part of the healing response nor a natural reaction to tissue injury. It is only a natural reaction to the detection of such molecules as bacterial lipopolysaccharides; the generic signature of bacteria. If there is no breach of a barrier, allowing for the influx of bacteria’such as in blunt injuries or sunburn?inflammation is inappropriate, and it does not happen to me anymore, nor anyone who gets enough glycine in their diet.”
The inappropriate inflammation really seems to be an extremely important issue in most diseases, not only metabolic syndrome. That’s probably a reason why glycine seems to be helpful for almost every kind of disease (even dental caries). And similar effects with carnosine/histidine and many other things. Ray Peat often mentions “essential fatty acid deficiency”, because that’s one way of suppressing the inappropriate inflammation.
Vladimir, I have a Beta-alanine supplement that includes some histidine.
Would the Beta-alanine be beneficial to boost carnosine, and would that supplement also be a good source of histidine vs. a pure histidine?
I don’t have the answers to this question.
All I “know”:
– Beta-alanine increases muscle carnosine levels (not necessarily plasma carnosine)
– I haven’t seen any studies showing anti-inflammatory effects from beta-alanine (anybody else?) but it might improve functioning and decrease fatigue
I think both options are probably good. Histidine alone, or with beta-alanine.
Hi, thanks for the post. So how exactly does sugar and fat raise endotoxins and how do we prevent this? Also arent endotoxins only a problem if u have a permeable gut?
I haven’t investigated this very carefully yet, but I think that sugar and fat have completely different mechanisms.
The absorption of dietary fat seems to automatically lead to absorption of some endotoxin (lipopolysaccharides) as well. Some of the endotoxin load seems to be neutralized by chylomicrons and LDL, but still there are studies showing that high amounts of fat lead to postprandial endotoxin spikes and inflammation.
If you look at the “Extra references” list, you can find some papers on this topic. One of the earliest papers I saw on this topic was this one:
Originally I found this idea from Jamie Scott’s blog “That Paleo Guy”:
“Dietary fats are digested and absorbed by the enterocytes and packaged into chylomicrons. These chylomicrons are pushed out of the enterocytes to the spaces between each of these cells (the intercellular space, funnily enough), where they tend to stack up on each other, stretching these spaces out. They are restricted from moving any further by a membrane that the enterocytes are anchored to ? the basement membrane. Eventually, something has to give, and the basement membrane ruptures allowing the chylomicrons containing long chain fatty acids to flow through to the lymph. But now we have a problem. There is a stretched gap between the cells lining the gut (enterocytes), and a breach in the basement membrane, giving access to anything sitting in the gut lumen (pathogens, food antigens, etc), through to the systemic circulation (via the lymph system).”
I don’t think that sugar causes endotoxemia directly, but on a high-sugar diet, some of the fructose might go unabsorbed and promote small intestinal bacterial overgrowth (SIBO) which probably promotes endotoxemia.
I think if sugar has an effect its probably by feeding gram negative bacteria that produce endotoxins. Paul jaminet has an interesting perspective on the link between fat and endotoxins worth reading here – http://perfecthealthdiet.com/2011/01/short-term-effects-of-adding-carbs-to-very-low-carb-diets/
“Does this mean that one should avoid dietary fat?? No, because it turns out the body regulates the amount of endotoxin entering the body. So a high-fat diet causes the immune system to exert greater control over gut bacteria.”
I find it a bit strange (albeit typical) that SAFA is being single out. Endotoxins are fat soluble, so MUFAS and PUFAS should have the same effect.
Here are my speculations why they often focus on SAFA instead of “fats”:
1) In cell cultures, SAFA (but not MUFA/PUFA) can activate TLR4 even if there is no endotoxin.
2) Many PUFA sources (such as olive oil) have significant amounts of polyphenols/salicylates/vitamin E and other compounds that might protect from the inflammation caused by endotoxin.
That’s interesting. Under what conditions does it activate TLR4? I don’t really know anything about it but it seems like that might be a good thing, since TLR4 primes the innate immune system, presumably it would help keep the immune system stay alert to danger and aid immune function.
This is just speculation, but it also seems to me that fats transporting endotoxins isn’t necessarily a bad thing. Could it be that the fats are trying to contain the edotoxins so they can’t do any damage? and possibly try to put them through elimination channels? I actually thought it was only problematic when you have leaky gut and the endotoxins leak into the blood stream, causing immune reactions and potentially crossing the blood brain barrier to engender other mischief.
I think we would need to have studies showing that SAFA elevates both endotoxins and inflammation/immune reactions under normal conditions before we can assume it’s doing actual harm. Any thoughts?
“I think we would need to have studies showing that SAFA elevates both endotoxins and inflammation/immune reactions under normal conditions before we can assume it’s doing actual harm.”
I mostly agree with this idea. I’m not very good at explaining these things, but if you look at the references list and extra references list, there is some human data showing that “junk food” meals increase endotoxin/inflammation and then there are other papers showing that you can decrease the inflammation with orange juice, fiber or antioxidants. These papers, for example:
Low-carb diet might even decrease some pro-inflammatory cytokines despite very high SAFA intake. So definitely there are many factors.
I don’t know what’s the “evolutionary reason” for direct TLR4 activation by some SAFAs, but I think that “priming innate immunite system” could be one possibility. However, that’s just speculation.
But it seems that TLR4/CD14 is so closely related to western diseases and many people seem to be having the system overactive. I dunno whether Joel Brind is right, but here’s his way of explaining the benefits of glycine:
“But if the fire department comes running every time there is something minor, you wouldn’t be very happy! Having chronic inflammation is exactly the same thing! Your body’s natural ?fire department (inflammation) is running uncontrolled, causing damage and making you age prematurely! Luckily, your body has a natural regulator of chronic inflammation, and it is a simple amino acid called glycine.”
There are also some videos of him in YouTube:
Ray Peat seems to be saying that nowadays many people get exaggerated stress or inflammation reaction, because some of our physiological systems aren’t working correctly. He often blames the high intake of polyunsaturated fats but I’m not sure yet whether PUFAs are as harmful as he says.
Thanks for your replies. It sounds like we still need a lot more research before we can understand the mechanisms.
Do you know what happens to endotoxins when there are less bacteria to transport them? DO they just get eliminated?
sorry, I meant to say “do you know what happens to the endotoxins when there are less fats to transport them” not bacteria :p
Actually I just read another article written by you on thyroid hormone and heart disease. You point out some studies which show that SAFA protected rats from liver disease caused by endotoxemia and lipid peroxidation, so there’s definitely more to it. Actually you also mentioned that choline is protective of endotoxemia, perhaps that can partly explain those results? I know that choline protects rats from fatty liver disease on a high fat diet, and most SAFA’s are high in choline.
How exactly does choline protect against endotoxemia?
You also pointed some studies that indicate that fructose might be able to cause endotoxemia by promoting SIBO and increased intestinal permeability associated with fructose malabsorption.
Yea, I actually had even forgotten that my thyroid article also had a section about endotoxemia: http://valtsus.blogspot.fi/2013/08/thyroid-hormones-and-heart-disease_13.html
Chris Masterjohn has also written extensively about choline, but I don’t think that he mentions endotoxemia. He, though, mentions that choline is needed for lipoprotein synthesis (especially VLDL). Some lipoproteins (chylomicrons, LDL) protect against endotoxin.
I’m not sure, but I also think that choline could be metabolized to glycine. Or vice verse.
Gotta investigate that in the future. :)
I don’t think that choline explains those results, because in those rat studies (by Amin A. Nanji) the intake of choline didn’t change. Masterjohn has actually shown that SAFA might increase choline requirement more than PUFA.
At some point I had the idea that fructose+glucose is worse than sucrose, because I think there was a study paper showing less malabsorption with sucrose than with similar amount of fructose+glucose.
I will let you know how Sweetamine tastes. I just ordered the 14 day trial of the stuff.
Indeed, Vladimir! (Thanks for the great post, btw.) Indeed, the fact that inflammation is an inappropriate response to tissue injury does explain an awful lot of morbidity. Take cardiovascular disease, for example. The circulatory system is a high-pressure fluid system, which is therefore naturally characterized by turbulence at arterial branch points, especially places where the pressure is highest, e.g., where the coronary, carotid and renal arteries branch off. So micro-injuries happen naturally at those points all the time. But they are not supposed to get inflamed due to micro-injury, they are supposed to simply heal! Inflammation is only a first response to infection, like the fire department. If you have a fire in your home, the fire department will put it out, but their axes and hoses will also do lots of damage. Imagine if the fire department came every time you lit a fire on the stove to boil water! Well, that’s what’s going on inside your body if you are glycine-deficient, like most people are!
Inflammation is therefore part of the healing process like the fire department is part of the home repair industry! That’s why inflammation actually INHIBITS the healing process. Why should you have to put ice on a sprained ankle to make it heal properly? Should not your body not react appropriately–without inflammation–so it can heal efficiently? Well, that’s what happens if you have daily sweetamine or other glycine supplement. Yet this is so foreign to almost everyone’s actual experience that we have come to assume the body is acting appropriately when inflammation follows injury. Nope! It’s just a sign of glycine deficiency.
As an aside i am new to this blog and matt’s crazy ideas
As an aside i am new to this blog and matt’s crazy ideas :p is there an article that summarizes matt’s dietary principles well? So far the impression i have gotten is that he advises people to eat more calorie dense foods, especially carbs and sugar (even if its coming from refined junk food); but im sure theres much more to it than that.
Personally i eat a mostly phd diet, high in fat and calories and i dont worry about sugar or carbs from whole foods; but eating coco pops with white sugar on top doesnt sit well with me just to boost my metabolism…
I think Matt can better answer this question, but here are some of the main points (from my perspective):
It’s important to eat enough calories, because undereating might be harmful in the long run.
Dieting might initially feel very “stimulating”, but it can eventually lead to health problems related to low metabolic rate.
I have seen many people having these problems and I personally had a “burnout” a few years ago, after following a low-carb diet – even though I felt “perfect” when I started the diet.
If you are stressed, the sufficient calorie intake is easier to achieve with calorie dense foods. But that doesn’t necessarily mean that one should eat “junk food”.
2. Water and salf
If you are stressed, it might be helpful to limit fluid intake and increase sodium intake until you feel a little bit better.
This also applies to foods. Bread has low fluid content, while potato has a high fluid content.
I think that Diet Recovery 2 (or Eat for Heat) has quite good explanations for these recommendations.
There isn’t a lot of scientific data on these issues, but I think that many people have witnessed that Matt’s ideas do apply in the real life. That’s probably one reason why Matt’s books have so many five-star reviews on Amazon – there are many satisfied readers.
“Salf” should read “Salt”. :)
Sorry about the duplicate posts, it kept cutting off what i wrote.
Great post. I had not done glycine-specific research, but in my own research I kept running up against references to the potential protective effects of glycine. So your suggestions are in line with my own conclusions.
It makes a great deal of sense that glycine would be important when you consider that half the protein in most mammals is collagen, which is extremely glycine-rich. We mammals clearly need glycine.
Thanks for the insightful post, Vladimir.
Nice blog post!
I have a question:
Can I just supplement Glycine on its own to my diet or does it need to be balanced by other amino-acids?
I have a dairy allergy and don’t eat meat so my protein intake comes solely from vegetables. Meaning I’m not getting the balance of amino acids from gelatine.
So will Sweetamine, capsules or powder (~8g) still be beneficial to take?
I think it might be more “balanced” to eat glycine during meals, instead of “on an empty stomach”.
Even though I’ve seen tons of positive research on glycine, I’m still hesitant to say that “eating 8g of this supplement will help you”. Personally, I eat lower amounts (2-6 grams) of glycine daily though I also take 1 gram of histidine.
The main need for dietary intake of glycine is to balance the intake of the essential amino acid, methionine. Since methionine is essential, the body has lots of different pathways to salvage, reuse, recycle and regenerate methionine, the body being designed to withstand prolonged periods of low protein intake and fasting. But these days, in the Western industrialized world, we eat so much meat fish and poultry (muscle meats) that we typically eat 10-20 times the methionine we need. Therefore, after the typical high-protein meal, the liver switches gears (like it does after a high carb meal) and gets rid of methionine as fast as it can. Trouble is, there is only one pathway for the clearance of methionine–the enzyme glycine-N-methyltransferase, and it requires glycine. So, when we eat lots of meat fish and poultry–loaded with methionine–and throw away the parts loaded with glycine (bones and connective tissues), we cause a great imbalance: a substantial glycine deficiency. Since glycine is also the most important endogenous regulator of inflammation, our innate immune system becomes hypersensitive, reacting with inflammation to tissue damage and all sorts of irritants that should not activate it. So the short answer is, the need for glycine is determined by the diet, more than the body type, and by simply adding glycine, you can typically restore a proper balance without any other changes. That was my intent in designing sweetamine, and 8 grams per day seems to be about optimal for the typical person on a typical diet.
And I would also add that, before I created sweetamine, I took 40g/day of supplemental glycine for a month, testing my blood every week. I got my serum glycine level up from 300 micromolar (which is supposed to be the top of the normal range, but it’s really inadequate) to 700 micromolar, with no ill effects (and lots of benefits!). And after all, 8 grams per day is really about equal to the bones and connective tissues we usually throw away when eating meat fish and poultry. Remember, glycine is not a micronutrient that I am advocating the megadosage of, it is a bulk nutrient, and a small, water-soluble molecule that cycles through the body rather quickly (except the small proportion that ends up in the collagen, which turns over very slowly).
Joel, because my life is so busy, the idea of making large bats of glycine rich bone broth doesn’t sound plausible or easy, although we do eat oxtail every so often because of the taste and the price but I throw it in the oven and I don’t boil it for hours. I like the idea of supplementing glycine into my family’s diet because we are a steak and potatoes; and pasta and ground beef kind of family. Is there a way of supplementing small amounts in smoothies for the whole family or is this really a specific one person kind of supplementation? BTW Sweetamine is not available in the country I live in although I can get high quality pure glycine powder.
We eat “10 to 20 times as much methionine as we need”…seriously? We need roughly 1 gram of protein per kg of body weightto achieve nitrogen balance, while an athlete may need almost twice that to optimize muscle building. Conservatively an 80 kg male might need 80 grams of protein a day, about 300 to 400 grams of meat. I dont know anyone who eats 10 to 20 times 300 to 400 grams of meat a day…yes we need glycine to detoxify excess methionine but dont be hyperbolic, and thats certainly not the only function of glycine, it has benefits independent of methionine intake.
Protein requirements are a little more nuanced than that. http://180degreehealth.com/how-much-protein-do-you-need-to-build-muscle/
Joel, I’m eating a vegan diet and so am probably not getting a lot of methionine. Will 8g glcyine still be beneficial or even neccessary for me?
How do you use red or infared light to help metabolism and thyroid… do you have to go to a doc? Can you do it to yourself at home?
Megan, I’m not expert but read Vladimir’s article (link below) on red light therapy and in the comments section of that article there are a few links for DYI. In short, yes you can do it at home but most of the research is on cold lasers and so we don’t know if heat lamps and red light bulbs work as well.
In some countries, doctors and some other health entrepreneurs use LLLT (low level laser therapy) devices for some diseases. That’s the “approved” form of near-infrared light therapy.
On the other hand, John Harvey Kellogg and others reported good results with incandescent lamps, and it’s completely possible that you don’t need expensive LLLT devices to achieve the same effect. Ray Peat also recommends incandescent bulbs and heat lamps.
There’s a lot of discussion about the dosages of near-infrared light and I still have no idea what’s the optimal dose.
I have speculated about these things in my article on red and near-infrared light: http://valtsus.blogspot.fi/2013/11/therapeutic-effects-of-red-light-and.html
If you join “Ray Peat Fans” or “Ray Peat Inspired” group in Facebook, you can find discussions about this issue.
Gelatin and Glycine eh? I always knew there was a real reason for my deep love of Haribos. HUZZAH!
Great article! Re: point #2…. I’m confused about the difference between near-infrared light and far-infrared light. Is one better than the other? Some health gurus (Mercola) say far-infrared. Thanks.
Only the wavelengths of 600-1000nm activate the mitochondrial enzyme “cytochrome c oxidase”.
600-700nm is red light.
700-1000nm is near-infrared light.
Far-infrared (FIR) lamps might have a nice warming effect, but it doesn’t have the energy-promoting effect on mitochondria, because of too long wavelengths.
Adding gelatin (glycine) into chicken broth and including more bone stocks in my diet has helped reduce my inflammation and increase my metabolism. I am so thankful for certain bloggers and all that they have contributed to helping others. You are saving my life! Keep the info coming!
Nice to hear that. Thanks Holly!
Thank you very much for this article – very informative and exciting though I have a personal worry and question about glycine. I have on a number of occasions tried to take the Great Lakes beef gelatin powder supplement and it always gave me insomnia, even just a 1/2 teaspoon first thing in the morning. Does this preclude me from trying glycine? Does this bad effect from gelatin mean I need to fix something else?
Here is a link to the amino acid profile of gelatin in case anyone is interested. This can vary based on the source of the gelatin. Glycine at 21.4% is 9% over the next highest amino acid,proline (18 amino acids in all). Histidine comes in at 0.8%
In researching glycine a bit more around the web, some people say that it lowers your core body temp and that’s why it can help you sleep better. Does anyone know if this is true? I don’t need a lower body temp :)
I have tried taking a gelatin supplement and at first it was fine. I was taking a TBSP in my yogurt in the morning…after a couple of days I was so sick after taking it. I waited a couple of days tried again with a tsp, still sick, again a couple of days later with 1/4 tsp, sick again. I get nausea, sweatiness, heart palpitations…and weird kind of headache. It lasts for about an hour or so. Why would this be
I was taking a highly recommend Kosher beef hydrolyzed collagen supplement for about a week. I was taking 1TBSP in my yogurt in the morning along with some toast and fruit. Then I started to become very sick after eating it. So over a period of 2 weeks I reduced it to a 1/4 tsp and still experienced side effects, such as nausea, sweatiness, heart palpitations and a weird headache. These symptoms last about an hour to hour and a half. But I end up with a bad stomach ache, bloating, and tiredness for the rest of the day. I am not allergic to beef. Why would this be happening?
That sounds strange… I don’t know.
But if it doesn’t work for you, then it might be wise to avoid it despite the positive rodent study results. :)
It may be that the hydrolized gelatin has a high percentage of free glutamate (e.g. MSG). I’ve known I was sensitive to MSG many years ago, but it was only a couple of years ago I discovered some of the other places it’s hidden. I even tossed all of my supplements that were in gelatin capsules.
You might want to look for some “regular” or non-hydrolized gelatin, perhaps organic? I may do the same thing myself.
I, too, got severe insomnia and heart palpitations from taking Great Lakes beef gelatin for two and a half months. I would go so far as to say it would have killed me if I hadn’t figured out it was the cause of and not the solution to those problems. The same thing even happened several months later just taking a magnesium glycinate supplement, so I am convinced glycine is seriously dangerous for some people. It is getting tiresome seeing all these enthusiastic endorsements of it, when such endorsements may lead a number of people toward the same serious harm we experienced from it.
That’s very interesting to hear.
I have been thinking that glycine should be quite safe, because in some clinical studies, schizophrenia patients have been using 60 grams a day. A magnesium glycinate tablet might contain 0.5 grams of glycine.
Let’s hope that many people won’t get adverse reactions.
Somebody just posted about similar adverse effects to my blog: http://valtsus.blogspot.fi/2013/12/glycine.html'showComment=1404395294735#c3665569102168722304
I really hope that if somebody else gets adverse effects from these nutrients, they understand to stop supplementation. But I assume it must be quite rare because I haven’t heard about this before (even in the scientific literature).
What I find interesting that some neurology researchers have been studying “glycine antagonists” for acute treatment of stroke, because they see glycine as an potential cause excitotoxicity.
However, it seems that many of “glycine antagonists” have failed, while real glycine seems to have protective effects against stroke
http://www.ncbi.nlm.nih.gov/pubmed/11277826 “This glycine antagonist joins the growing list of neuroprotectants that have not shown improved outcomes for patients with acute stroke, despite promising preclinical results.”
http://www.ncbi.nlm.nih.gov/pubmed/10629347 Reduced mortality, risk of disability and lipid peroxidation in the glycine treatment groups (low dose).
Transient arrhythmia from major glycine poisoning
We report the case of a 41-year-old ASA I patient who experienced during endometrial resection a transient idioventricular cardiac rhythm with hypotension related to a major glycine intoxication. The total volume of absorbed irrigating fluid was over six liters when these clinical signs occurred. The biological data were as following: Na = 89 mmol.L-1, Cl = 60 mmol.L-1 and osmolarity = 215 mOsm.L-1. Simultaneously, the glycine concentration in the plasma was 54.6 mmol.L-1, i.e 160 times higher than the normal value. The clinical course was unremarkable except vomiting. The treatment included only the administration of a diuretic agent, as the correction of the disorder took place spontaneously. The paucity of clinical symptoms when compared to the severity of the biological disorders explain why preventive measures are essential in this type of surgery.
I am also surprised at these negative reactions, and I would caution against blaming glycine when collagen preparations and Mg-glycinate have a lot more than just glycine in them. Of course there are rare genetic variants who cannot tolerate glycine, and I would imagine that, for example, a heterozygote carrier of NKH (non-ketotic hyperglycinemia) might have this trouble. In fact, I would recommend the opposite kind of supplement–methionine or SAMe–as a way to help clear excess glycine from the body of people who have this variant of body chemistry. Zanolachino, it is good that you are trying to figure out your atypical reaction, and I would suggest you have your blood amino acid concentration profile determined. That should tell you if it’s actually the glycine that’s causing the trouble. Genetic profiling is also easy to do these days, to see if you have any atypical enzyme functions related to amino acid metabolism.
Joel, is there any reason to believe that glycine might be helpful for insomnia? Sleep is my achilles heel.
Also, shouldn’t we expect to see much less diseases of inflammation in cultures, like the Chinese, where organ meats, tendons, etc are eaten? Are there any studies that suggest that is the case?
Thanks for taking the time to answer our questions.
If you’re still reading comments, my experiences with glycine have never been good. I have treatment resistant rapid cycling/mixed state bipolar and years ago, read that glycine can tamp down mania, as well as improving sleep. Didn’t work for me. However, this year, after reading some new research on it, tried glycine,again, at night, 6 gm. I had severely disturbed sleep accompanied by vivid, strange and disturbing dreams. I’ll get my glycine from food(I eat fish, exclusively). A shrimp, salmon and flounder meal contains about 3 gms of glycine and, yes, I know methionine is also there. Oh well…
Do you have any hypotheses as to why you respond in this way?
It’s the same for me with Mg glycinate (and gelatin).
I’m not content to say “if it doesn’t work for me, I’ll just steer clear” because I want to figure out what is wrong with me. This strange response to glycine would seem to be an important clue. I’m not screwing around with this stuff as a hobby; I’m trying to heal crippling health problems.
All I know is that Amy Yasko claims that glycine will push your brain further in the direction which already dominates, GABA or glutamate.
I don’t remember Sally Fallon recommending Glycine. Thanks anyway. Go go CLO!
Actually, Kaayla Daniel and Sally Fallon are soon publishing a book “Nourishing Broth: An Old-Fashioned Remedy for a Modern World” which will probably contain a lot of positive stuff about glycine.
Broth is a good source of collagen/gelatin, therefore also glycine.
“NOURISHING BROTH will continue the look at the culinary practices of our ancestors, and it will explain the immense health benefits of homemade bone broth due to the gelatin and collagen that is present in real bone broth (vs. broth made from powders).”
Could there be a possibility that ALL these things are correct/false in equal measure ? ? according to the metabolic typing theory some people need high fat/high protein in their diet, others need low fat/high carb and most people fall somewhere in between the two poles. That is why you can surf the net and come across a vegan doing fantastically well on 30 bananas a day and then flip to the next blog and find a carnivore thriving on organ meats and saturated fat.
What I cannot fathom is the TIME and EFFORT people are spending on trying to find a DEFINITIVE answer to this that can be applied the the human race as a whole! What a waste of time. I mean, how many articles, abstracts and papers does one have to wade through in order to find the truth?
The truth lies within the individual person, there can be no other way.
Why are we not spending our time trying to find out what works for us as individuals instead of getting involved in these mind-blowing abstracts that give us a brain freeze ? There is no universal theory that will work for all of us, all of the time and there is no point searching for it outside of our own personal experiences !!!!! I applaud this blog post for its scrupulous research and findings – which all seems very academic and bone fide but which unfortunately could probably be contested by so many people who have had so many different experiences on so many different diets over time.
Do you sometimes have the feeling you are falling deeper and deeper into information overload and have no way of getting out of it alive? Trust your own bodies, experiment, move forward and devise an eating plan that works for you and you alone. Don’t let the science or the diet gurus push you into thinking one way is inherently better than the next unless it works implicitly for you and you alone.
I’m pretty sure Vladimir is just letting us know about a few more items on the experimentation menu.
I’m also certain that temporarily thriving on an extreme diet isn’t very good evidence of anything, and any extreme diets that I “thrived on” eventually made me sick just like it does nearly all gurus of those diets (every guru eventually comes to a point where they have to choose between changing their diet or doubling down and getting very ill).
In fact, I think that could very well be the danger of trying to “figure out what works for you,” as what makes people feel great, have awesome energy, and lose weight in the short-term can have nasty long-term consequences, so it’s a slippery slope. I have preferred to direct people towards assessing metabolic feedback while experimenting rather than how they look or feel in isolation, which is more likely to send people careening in the wrong direction.
I agree that it’s very easy to go “wrong way” when you just start reading studies or health books, and ignore how you feel.
For example, Ray Peat often recommends orange juice (OJ) and he has studies to back up his recommendation, but in agreement with Matt’s “Eat for Heat” ideology (which is based on few studieS), I often feel worse when I drink OJ. Therefore diet doesn’t include high amounts of sugar or fruit juices.
I also noticed that for me, hugs/massages have more important short-term benefits than glycine. I started adding the physical aspect to my relationships before reading any research, because it simply felt good.
So, I’m suggesting that one should not blindly follow some dietary “ideologies”, but instead create some dietary habits that are based on your own experiences/feedback.
Personally i feel terrible restricting carbohydrates or fat, if i go on a low fat or low carb or low meat diet i feel unsatisfied, anxious, depressed etc. And i feel much better eating starch than simple carbohydrates, while other people seem fine on a low fat or high sugar diet. But as you point out just because individuals vary in their response that doesnt mean we should eat overly restrictive individualized diets either.
I have noticed that my body seems to have two different functional modes, which require different diets.
1) When I’m not very stressed, I can easily eat a lots of potatoes and root vegetables with extra fat, and there’s no problem drinking orange juice etc.
That’s when I don’t need the “Eat for Heat” recommendations.
2) But occasionally I start feeling stressed and then I really have to consume some starch+fat+sugar+calories and avoid the potatoes and other foods rich in potassium/water.
One good example “meal” could be 1-2 cheeseburgers with extra ketchup. If I have to drink something, my choice would be whole milk or milk chocolate.
The “junk meal” restores my wellbeing and appetite, and after that I can continue eating a normal diet.
I expect that I’ll become healthier in the near future, and possibly I won’t have the junk food/”mode two” issue anymore. Time will tell…
i applaud you on this!! summarised exactly and succinctly- have your own blog girl- id read it!!! no disrespect to constant education and research on nutrition- but a voice of reason like this is HIGHLY IMPORTANT for the people reading
that was to louisa!!!!
i’ve bouhgt me this IR Lamp:
My question is now, from what distance should i use this lamp??
Actually I don’t know what’s the optimal distance (or duration). Some wound healing studies have shown a “biphasic” effect, in which high doses of light are harmful. But on the other hand there are some other studies showing more benefit from higher dose and longer duration. I think that Ray Peat advices that “more is better”, when using incandescent lamps.
Here’s my old comment from “Ray Peat Inspired” group in Facebook:
“Hmm… They often say that quite a low dose of red/infrared is best, because there is a “biphasic dose response” and if you use too high dose of light, you do not get any benefits.
On the other hand, I think that many of these studies have evaluated low level laser treatment for wound healing, and it could be that optimal dose for wound healing is not same as the optimal dose for healthy metabolism.
In this study, 1250J was the dose delivered to knee osteoarthritis patients (high-intensity laser was better than low-intensity) and the results were quite good. If you use some heat lamps… It takes some time to get a similar amount of energy (in the 600-1000nm range).
In rat arthritis 30J/cm2 dose was better than 3J/cm2, and on both doses, the better effect was actually seen when the power was smaller, so the treatment took more time.
Personally, I used to keep 250W heat lamp at a distance of 50-80cm from me, but nowadays I prefer like 120-200cm. Usually for 30-60 minutes but sometimes I even sleep with the light on (using a sleep mask).
Hi Vladimir Heiskanen, Have you ever taken thyroid hormone (dessicated, T3, ETC?)? Have you ever used red light therapy?
I’m a medical doctor and 5 years ago, I too was reading these cool scientific and medical journals about thyroid and red light, just like you are doing now. I was convinced they are the great healers. Then I started trying them on patients and on myself. I started my patients on conservative small doses of T3 (1 mcg a few times per day) or dessicated thyroid (1/2 grain and slowly raising). It backfired in about 95% of all my patients. My patients gained significant weight, became constipated, fatigued, depressed. I then went on to the promised land of red light. Bought several hundred W of red incandescent bulbs and installed them in my home. Even 5 minutes under red light caused stress, insomnia, bloating and other symptoms of excess nitric oxide. Many of my patients also reported how red light made them feel bad, DESPITE the fact that these magical studies claim that red light reduces nitric oxide.
In conclusion Vladimir Heiskanen, why don’t you start taking T3 or dessicated thyroid, so you have some person experience with the substance matter?? What you are doing now is just convincing innocent people to start taking a substance which will probably make them sick, because you just happened to read something on the internet. Which, Vladimir Heiskanen, is very immature and naive.
Hi Dustin, thanks for the comment.
I haven’t used thyroid medication. I would try it, but in my country it’s very difficult to get the prescription, and the most pro-thyroid doctors are very popular and therefore expensive.
However, I have talked to a local doctor who has prescribed T3 to more than a hundred patients. He said that it doesn’t work for everybody, but sometimes it gives extremely good results. I also know many thyroid patients and have read a lot of studies and user experiences on the internet.
However, it might be that some of the negative experiences just don’t get a lot of attention. Maybe because those patients aren’t very interested of sharing their unsuccessful experiences.
I have heard from quite many people that T3 alone has been problematic for them, but adding cortisol (hydrocortisone) has made it possible to continue the treatment.
In quite many recent studies, ubiquinone (CoQ10) has had some analogous effects with thyroid (or T3). In fibromyalgia patients, it increases intracellular ATP and decreases MDA and affects many markers positively (NLRP3, IL-6, IL-8, AMPK, PGC-1a, SOD1, SOD2, NRF1, IL-1?, TNF-?). Many of these markers are related with energy-metabolism. For some people, it could be a safer alternative to thyroid, but I haven’t heard many actual user experiences yet.
I have been using a 250W heat lamp. My personal experience is quite positive, and many people in Ray Peat groups have also reported significant benefits. In addition, there are also those positive research articles so I suppose red light shouldn’t be very harmful for most of us.
However, I have noticed that every kind of electric light seems to have a stimulating effect that might worsen the condition of some sensitive people. When I had a burnout at the end of high school, I could get migraine from normal indoor lighting. I think that red light would also have been harmful. But I don’t have those problems anymore and red light also doesn’t cause problems.
I have been thinking about the possibility that increased metabolism by red light -stimulated tissues could be bad for people who have hypoglycemia tendencies, because increased tissue metabolism could increase blood sugar requirements.
I think that these issues are definitely much more complicated than these articles of mine (and others) suggest. I have been thinking that I should write much more extensive articles and discuss the mechanisms and the possible harms of these treatments more carefully, but I have the gut feeling that almost nobody would read such long articles. That’s why I keep these articles annoyingly simple (and still I think that some people think they are too complicated).
But I still believe that these articles might provide more benefit than harm. And most of the people here are wise enough to stop the treatments that seem to cause harm for them. However, I think that adding some kind of a disclaimer emphasizing caution with all kinds of new treatment options would be useful.
I wish your blog articles were longer vlad, i enjoy reading them :)
If you are right and it is exacerbating hypoglycemic tendencies then perhaps the disclaimer should be too eat more carbohydrates and total calories like matt already recommends along with taking t3 and using red lights.
Oh and it’s ‘subject matter’ dr. superior, not ‘substance matter’ :p
The negative effects from incandescent bulbs you describe could be due to non-IR wavelengths also emitted. I have two halogen heat lamps, a Beurer with a ceramic glass plate, which filters out some wavelengths, and a Philips. The Philips gives me the same symptoms you mention here, but the Beurer does not.
However, according to Lawrence Wilson M.D. some other negative reactions (such as irritability in my case) are due to IR light causing the mobilisation of toxic substances- an unwelcome but necessary part of getting them eliminated.
I should also mention I have experienced many positive results from use of the Beurer, including amelioration of hay fever symptoms, relief from sleep onset and sleep maintenance insomnia, relief from sinus pain, back pain, and speeded healing of wounds and viral infections.
Dustin is right. T3 is the new low carb.
Vladimir Heiskanen is a crappy scientist/blogger/whatever, since he doesn’t have personal experience with the things he recommends. At least Ray Peat has tried all things he talks about, including T3, DHEA, progesterone and so forth
It appears that Jennifer has not read all that Vladimir has posted as comments following his article, wherein he opines on optimal glycine supplementation amounts, based on his personal experience, for example. In any case, personal attacks merely reflect poorly on the critic.
Since starting glycine supplementation, I have been getting more smiles from the beautiful girls. And I got accepted into the faculty of medicine (to study dentistry). Coincidence? ;)
Yea, I’m somewhat a crappy scientist/whatever because I don’t have much personal experience, but I think that one can also achieve a lot of knowledge by reading enough – especially if he can also discuss the issues with people who have the personal experience. I think I’m quite good at reading research, and I read very much so it’s giving me a wider perspective/context than most people have.
In this article, I didn’t mention thyroid medication. I’m usuaslly talking mostly about “thyroid function”, which is a physiological issue affected by many things beyond medications (nutrition, light, immune system, stress).
I think NDT (natural desiccated thyroid) is a potentially beneficial supplement for many people, but I would like to emphasize the importance of other lifestyle factors.
I’d say that is important to start understanding what things are causing the “thyroid insufficiency” epidemic (Broda Barnes, Jacques Hertoghe, Mark Starr, etc.). Broda Barnes would have been interested of putting 40% of the population on thyroid medication, but for me it doesn’t sound very logical.
I’ve been reading literature on fibromyalgia which has many similarities with hypothyroidism, as John C. Lowe has noted: http://www.thyroidscience.com/reviews/lowe.yellin.6.17.08/ithr.review.6.17.08.pdf
Recently I read a paper by Morris&Maes, which suggests that there are a lot of mechanisms by which inflammation and oxidative stress can lead to low metabolism: http://www.ncbi.nlm.nih.gov/pubmed/24557875
If inflammation related to endotoxemia/TLR4 is a fundamental factor in metabolic syndrome, there is a possibility that similar things could be also causing fibromyalgia and “type 2 hypothyroidism”. If that’s true, then it might be a very positive thing that I’m trying to start some discussion on glycine and histidine here.
You get more smiles from beautiful girls? What a jerk! What the hell does that mean? That ‘girls’ you deem beautiful are more important than those you deem not beautiful? And that now those people you think are so special notice you, you now think you are the man you always wanted to be?
You don’t deserve to have a respectable position, you are a shallow egotistical dweeb.
If you are joking Woo, that is quite funny. If not, please kill yourself.
Wow- really? I object to yet another man getting all excited about beautiful girls enough that he has to brag about it? Don’t you think that being treated differently based on how you look is damaging? Just because I object to preferential treatment based on looks I should “kill myself”.
All I did was call the guy out. I didn’t say he should kill himself or anything close.
So no, I was not joking but no I’m not going to hurt myself because you said I should. Who do you think you are to say that to someone. I’ll tell you that I am sick of people who did nothing but be born a certain way being treated better or worse because of the genes they were born with. For someone to get happy about a beautiful person looking at them is one thing but then to advertise it is another and IS shallow. GO f yourself Matt.
Because Vladimir was joking Woo, and you took it seriously, which means you must have no sense of humor or be a complete idiot. The former being a particularly strong reason to consider offing yourself, the latter is more likely to be a hereditary issue and it is indeed tragic to be ridiculed for something largely out of your control.
You really think he was attributing smiles from girls and getting accepted into dental school to taking 6 grams of glycine per day?
It’s a joke. Sarcasm. Got it? Relax. You don’t have to kill yourself, but please at least slap yourself for not picking up on that.
Whether that was a joke by Vladimir really isn’t the point. It is still elevating “beautiful girls”. And if glycine is in fact helping one’s metabolism thus making yourself more attractive (more muscle, better skin…)and smarter, then why is it such a stretch to attribute attention by pretty women and getting a position from taking glycine.
Maybe I missed the “joke” but that is because it isn’t funny.
I was mostly joking about the importance of n=1 experiences.
It doesn’t make me much more knowledgeable if I start taking a supplement (thyroid/T3/red light/glycine) and see what happens after taking the supplement for some time.
In the recent weeks, many improvements have happened in my life (school, relationships, health). I noticed many of these positive changes after I started taking glycine (and histidine).
But the improvements could also be caused by increased potato intake, my new friendships, summer or any other thing. Or it could be just some “random” variation.
If we look at the studies, they give a little bit more conclusive knowledge than the short-term n=1 experiences.
Regarding the women and being a “jerk”.
According to Baumeister&Vohs, it might actually be beneficial to be a jerk.
“Although this may be considered an unflattering characterization, and it cannot at present be considered a proven fact, we have found no evidence to contradict the basic general principle that men will do whatever is required in order to obtain sex, and perhaps not a great deal more. (One of us characterized this in a previous work as, ?If women would stop sleeping with jerks, men would stop being jerks.)”
I could be a jerk, but I think that simply talking about “beautiful women” doesn’t make me one.
Physical appearance, social status, physical&mental health and many other things can influence the (sexual) attractiveness of an individual a lot, and I think that the attraction is quite a “subconscious” thing instead of being a rational choice, and that’s why I don’t think it’s very helpful to accuse somebody of being attracted to healthy/beautiful/interesting people.
And I think that almost everybody is an “victim” here.
After I had a burnout in high school, I was not “important” for most of the girls that seemed interesting to me. The girls chose other men instead me. Should I accuse them of seeing me as less important than other guys? No, especially because attraction is not a rational choice.
 Baumeister&Vohs: Sexual Economics, Culture, Men, and Modern Sexual Trends (2012) http://link.springer.com/article/10.1007%2Fs12115-012-9596-y
I grew a goatee and get many more smiles from sexy women, young and mature. Pretty good for a 69 year old, lol. I might add thyroid back into the mix! Smiles are great but I want to get beyond the smile phase. ;)
You dont have to kill yourself woo, but at least punch yourself in the head until some sense gets knocked in :)
I’m not really sure why someone has to be using T3 or NDT to recommend it if they’ve researched it and deduct that it may be helpful for some people.
I wonder if Ray Peat has used progesterone up his vag as I heard him recommend to a female caller on radio once? I’m no scientist, but I doubt it.
I think it’s good to be quite cynical about the things you read and never take anyone’s words or experience as gospel. But this article seemed fairly well researched and helpful.
Of course you are quite right, Tanya. As for me, it was appropriate for me to try glycine supplementation myself–especially before I started to sell it as a product (sweetamine), but I have, for example, long recommended DHEA for postmenopausal women and never tried it myself. (Of course, DHEA is good for men and women, but my endogenous DHEA–measured as DHEA sulfate–has always been on the high side of normal, so I knew that taking it myself would make no measurable difference.)The bottom line is that self-experimentation is neither a necessary nor sufficient condition for recommending anything; it is often part of a good, scientific approach, but not necessarily.
Tanya – well said and funny. I see Vladimir as trying to help in a very sincere way. I don’t think glycine would help me, though I think understanding why it would help some people would also help to understand why it wouldn’t help me, thereby helping me find out what is f’d-up in my body. I see all of this kind of research as beneficial.
So, is it possible to supplement vitamin k2 to a 2 year old? This is the brand I can get here in Argentina which is MK7
I plan on taking it myself and my husband will also, I would like to supplement a little to my son but I don’t want to endanger him by overdosing :-S.
I don’t actually have any idea. I hope that somebody else can answer that question.
As far as the literature is concerned there is no toxic dose of vitamin k, so if you use a reasonable dose theres no reason to worry.
E. Rose~ After reading about all the positive effects of Vit K in different forms, I decided to try supplementing with it. I first took MK7. Honestly, it was one of the scariest reactions I’ve experienced from a supplement. I have zero idea why I reacted so. But, I honestly thought my brain was going to explode. Horrible, horrible insomnia with with actual ‘brain pain’ but not in the form of a headache. Difficult to explain.
Then, an ND placed me on a calcium product (which I really didn’t want to take but did) which included MK4. It was at a lower dose. It didn’t have the same negative effect right away but within a short period of time, the insomnia became awful.
I’ve tried to find what might cause my reaction but haven’t been able to find any pertinent information. But, from my own personal experience I’d say, be very careful especially considering giving this in any form to a child, especially a toddler.
I’m curious if one should be concerned about inflammation if their CRP levels are always low. Is it definitive that you don’t have any inflammation if CRP test is low? Or should we take glycine anyway?
Just going by personal experience here, Cathy, but before I started supplementing with glycine, my diet was otherwise rich in anti-inflammatory foods and my CRP was always barely measurable. However, I still suffered from the usual inflammatory effects of strenuous exercise, blunt injury, sunburn, and some measure of chronic periodontal inflammation. All that disappeared with glycine, so clearly, CRP is not the whole story (or a marker for the whole story).
Hmm, well, I tried the glycine for four straight nights. It may have ‘slightly’ improved my sleep, but it was not profound. I did however get a bit constipated, and it left me a bit sluggish the next day. Everyone is different!
Here are the top food sources for glycine, showing the exact grams of glycine per 100g of the food.