CLnA, the "Omega-3 Variety" of CLA from Pomegranate & Co, Has Potent Anti-Obesity Effects and the Potential to Become More Than Just Another Anti-Diabetes Drug.

Image 1: Pomegranate - I loved to eat them even before I realized that their seeds are the #1 dietary source (83%) of punic acid.

While more and more people are beginning to grasp the notion that with (naturally occurring) fats - as with everything else in life - there is no simple "good" and "bad", no clearcut "black" and "white" and no definite "beneficial" and "detrimental". The number of different fatty acids and their respective effects on the human metabolism is so vast that it is pretty hard to keep track of all those varieties of saturated and unsaturated carboxylic acids. I would thusly not be surprised if you simply assumed that the "n" in the headline of this blogpost was a type that had slipped in because poor Dr.Andro is chronically stressed from Christmas shopping... well, while the latter is actually correct, the former is not: CLnA is actually the omega-3 variety of the famous conjugated linoic acid (CLA), which in and out of itself is not a single but a group of 28 different trans- and cis-isomers that occur in our diet mainly in the shape of high and full-fat meat and dairy products.

CLnA - Conjugated Linolenic Acid is not a typo ;-)

Within the last couple of years even the medical establishment has come to realize that the chronic omega-6 (n6: linolic acid) overload in our diet is killing us. The "heart-healthy" PUFAs have now become the more and less heart-healthy PUFAs with the totally healthy *rofl* omega-3s and the not just as healthy omega-6s - both, of course, still totally "essential" and WAY better than saturated fats,... (attention: the afore statements are full or irony! Saturated fats are of course NOT the bad guys. Sorry, David if that lead to confusion)... but I am getting derailed, here. So let's get to the point. What every reasonable person appears to agree on, these days, is that we have to lower the ratio of n6:n3 fatty acids in our diets. Now, I am asking you: Has it ever occured to you that CLA essentially is an omega-6 fatty acid? I mean its conjugated linoleic acid - "linoleic" as in omega 6 = linoleic acid! Probably not, right? The reason for that is yet (hopefully ;-) not that you are dump, but simply that the existence of an omega-3 "variety of CLA", namely conjugated linolenic acid, or short, CLnA, is something about which you will only hear, when you read blogs (such as the SuppVersity ;-), which do not stick to copying, pasting and commenting the stuff the authors have read on one of the major news-portals.

Table 1: CLnA isomer content in natural sources (data adapted from Hennesey. 2011)

From a molecular perspective,  CLnA isomers combine the conjugated double bond system of the classic conjugated linolic acid, you know, with the octadecatrienoic fatty acid (C18:3) structure of omega-3s, i.e. linolenic acid. Interestingly, this make-up confers these fatty acids with a high bio-active potential. Now, while this may sound like one of the frankenfood test-tube results of the gene-technology laboratories of Monsanto, we know at least 10 CLnA isomers which occur naturally in foodstuff or as byproduct of fermention processes (cf. table 1).

Adiposity, hyperlipidemia, cancer - CLnAs could help with all!

Image 2: Even if CLnAs would just prevent obesity, this illustration I borrowed from multiplemyelomalifeexpectancy.tk, shows that not being / getting obese alone would prevent a plethora of related maladies. Such as kidney failure, arthritis, gallbladder disease, infertility, asthma, fatty liver disease, sleep apnoea, depression, heart disease, hyperlipidemia, diabetes,... basically every major ailment the increasingly obese convenience society of the Western hemisphere is suffering from.

Due to their anti-adipogenic (meaning preventing the accumulation of body fat) effects CLnA fatty acids have been investigated as potential candidates for the treatment of the obesity epidemic for quite some time, now (Hennesey. 2011). In a 2002 article that was published in the Journal of Applied Biochemistry and Biotechnology, Nishimura et al. report that CLnA isomers exert apoptotic effects on mouse preadipocyte 3T3-L1 cell - or, in plain English, incubation with CLnA did not only hinder the "pubertal" fat cells from becoming mature adipocytes, it actually killed them. In vivo studies with rodents, such as Arao et al. (2004), where the administration of a diet that was enriched with 1% pomegrenate seed oil lead to a 27% reductin in omental white adipose tissue, were able to confirm the "rodent-real world signficance" of these test-tube results.

Other studies showed a normalization of hyperlipidemia in rodent models of the metabolic syndrome and a hand full of studies have explored the usage of CLnA isomers as cytotoxins in the treatment of cancer. In their concise review of the literature, Hennesey, et al. thusly rightly conclude that with their "potent inflammatory and immune modulating properties", their ability to "reduce the risk of obesity, improve cardiovascular health, and mediate strong anti-carcinogenic activity", the use of CLnA isomers or dietary enrichments could offer treatment strategies for pathologies, which "represent some of the greatest mortality risks to humans in the Western world and have been inextricably linked with diet" (Hennesey. 2011).

Adding diabetes to the list of potential targets for CLnA

For today, we are however going to focus on the most recent result from the research front: The effects of CLnAs on diabetes, or, to be precise, the increases in blood glucose, and decreases in anti-oxidant capacity that go hand in hand with the latter. In a recently published study (Saha. 2011), Siddhartha S. Saha and Mahua Ghosh from the Department of Chemical Technology at the University College of Science and Technology of the University of Calcutta (I don't have to tell you that this is in India, do I?) injected male albino lab rats with 60mg/kg streptozotocin (STZ) - this is a common and well-established method to induce a metabolic state that serves as a model of type II diabetes - and fed them diets that contained either no, or 0.5% of the total fat in the form of alpha-eleostearic acid (from bitter gourd, cf. table 1) or punic acid (which was in this case taken from snake gourd oil, but could as well have been extracted from the eponymous pomegrenate, cf. table 1).

Figure 1: Relative blood glucose levels vs. non-STZ injected control in streptozotocin injected rats over the course of the dietary intervention (data calculated based on Saha. 2011)

As you can see in figure 1, this 100% natural "food additive" had a more than pronounced effect on the +300% (vs. non STZ-injected control) elevated blood glucose levels of the "type-2 diabetic" rodents.

Figure 2: Relative level of lipid peroxidation (left) and total antioxidant capacity (right) levels vs. non-STZ injected control in streptozotocin injected rats after the 28-day dietary intervention (data calculated based on Saha. 2011)

And while the glucose levels were still 150% above those of the healthy control levels, the streptozotocin-induced lipid peroxidation in plasma, pancreas and erythrocytes of the lab animals was ameliorated by the snake gourd oil treatment (remember that is the stuff from pomegranate) and even reversed by the bitter gourd diet. Judged by the standardized FRAP assay, the "diabetic animals" that were fed a diet that contained 0.1% alpha-eleostearic acid (of the total diet, which had 20% fat) even exhibited a 10% greater total antioxidant capacity than the totally healthy control!

Figure 3: Relative expression of inflammatory cytokines, TNF-alpha and interleukin 6 in plasma capacity (right) levels vs. non-STZ injected control in streptozotocin injected rats after the 28-day dietary intervention (data calculated based on Saha. 2011)

Snake gourd oil, on the other hand, exhibited more profound effects on the elevated TNF-alpha, interleukin-6 and NF-kappaB levels of the STZ-treated rodents (cf. figure 2) and thus, at least this is my humble opinion, render punic acid the overall more promising agent with respect to the treatment of all sorts of inflammatory (or related diseases). After all, disturbances in the regulation of the nuclear factor kappa-light-chain-enhancer of activated B cells  (NF-kappaB) and the downstream over-expression of TNF-alpha and IL-6 are hallmark features of allmost all the aforementioned ailments of the increasingly obese western convenience society. This is also why I am quite certain that we are going to hear much more about the CLnAs in the month to come... and I guess, I don't have to tell you that right here, at the SuppVersity, is where you will read about respective studies first!

Artichoke Leaves Diabetes No Chance: Thistle Qualifies as Anti-Oxidant, Carb Blocker, Digestive Help & Diabesity Drug

Boiled Artichokes slow down the absorption of glucose and minimize the insulin + glucose surges (Nomikos. 2007)

This article has made quite a remarkable transformation. It started as a Facebook Short News Item, was upgraded to a mini-article for the SuppVersity Short News and, when I realized that those green thistles have surprisingly diverse beneficial effects on human health, eventually became the regular SuppVersity Article you are about to read, right now.

Artichoke leaves the future of diabesity treatment!?

I have to admit, I am not exactly and artichole expert, but I was still surprised that the paper Joanna Magielse and her colleagues from the University of Antwerp are about to publish in the scientific journal Food & Function claims to be the first to investigate the beneficial health effects of artichoke leave extracts on diabetes-induced oxidation in vivo.

I mean, we all have seen the broad range of artichoke supplements on the shelves; and my brief review of the literature yielded studies from the mid 1920s discussing how beneficial artichoke can be for patients with type II diabetes (Root. 1925).

When I kept digging through the currently available literature, though, I had to realize that the vast majority of the in-vivo studies dealt with the anti-cholesterol (Wider. 2013) and digestive benefits (Marakis. 2002) of artichokes and their leaf extracts (ALE). The proven anti-oxidant effects of its major polyphenolic constituents (Zapolska-Downar. 2002;  Betancor-Fernandez. 2003; Jimenez-Escrig. 2003; Menghini. 2010), on the other hand, haven't been tested in either animals or humans with type II diabetes. The rodent-experiment the Belgian researchers describe in the paper at hand is thus probably in fact the first to investigate the anti-oxidative effects ALE in an in-vivo scenario.

More about chlorogenic acid.

What are the active ingredients in artichoke leaves? Mono- and dicaffeoylquinic acids were the major polyphenolic constituents: The total caffeoylquinic acid (CQA) content was 1.5%, with chlorogenic acid (CGA) being most abundant (0.30%), next to cynarin (0.12%) and several isomerization products of CGA (the sum of which was 0.75%), including neo- and crypto-CGA and dicaffeoylquinic acids. Luteolin-7-O-glucoside was the major flavonoid present.

Over the course of 3 weeks the rodents who had been injected with streptozotocin (STZ) to induce a diabetic phenotype that is commonly and successfully used as a model for type II diabetes in man consumed either

• Why 0.2g/kg BW? This is the rodent equivalent of a well-tolerated amount of 2g/day that has been used for treatment of hypercholesterolemia and digestive complaints (Englisch. 2000; Holtmann. 2003; Barnes. 2007).
  0.2g/kg BW of artichoke extract (CYN1),
• 1g/kg BW of artichoke extract (CYN2),
• 50mg/kg BW alpha-tocopherol-acetate (VIT E),

or no supplement at all. To make sure to have an appropriate reference, a fifth non-streptozotocin injected group served as a healthy control. In contrast to their their com-rats (sorry, I could not resist) who had blood glucose levels of 250mg/kg, the control rats started into the 3-week treatment phase with normal (=healthy) blood glucose levels and inflammation.

Learn About Artichoke Alternatives for Glucose Management:

Lifestyle Changes

ALA, GABA, Taurine & Co.

Berberine, Banaba & Co.

Cinnamon, Curcumin & Co.

Lemon, Starch, Coffee & Co.

Chlorogenic acid, fucoxanthin & Co.

To determine the effects the provision of artichoke leaves would have on the baseline inflammation of the diabetic rats, the researchers measured the plasma malondialdehyde (MDA) and urinary 8-hydroxydeoxyguanosine (8-OHdG). The status of plasma coenzyme Q9(CoQ9, necessary for the biosynthesis of coq10 increases indicate lower coQ10 levels) and erythrocyte reduced glutathione (GSH), on the other hand, were used as indicators of the state of the endogenous antioxidative defense system.

Figure 1: MDA, 8-OHdG, CoQ9 and GSH levels expressed as rel. difference to control (Magielse. 2013)

With the information from the previous paragraph, even a rocket scientist without a clue of biology will recognize that the buffered MDA,8-OHdG and coQ10 and GSH levels (the further away from the x-axis the more "disturbed" they are compared to the CON group), indicate that the artichoke leave extract did what the were not 100% sure it would to: It survived the passage through the gastrointestinal tract and wasn't extensively metabolized by colonic microflora or liver phase II enzymes, as it is the case for other potent in-vitro antioxidants like reseveratrol.

What's the mechanism and what do we already know about artichoke?

With respect to the underlying mechanism that could explain the improvements the researchers observed in the study at hand, Magielse et al. point out that...

"...it should be emphasized that not only direct antioxidant actions, but also indirect mechanisms affecting gene expression of inflammatory pathways and modulating antioxidant enzyme synthesis have been reported for polyphenols and may contribute to the reduction of oxidative stress." (Magielse. 2013)

In that, the scientists are referring to the previously established beneficial effects on lipid metabolism and glucose absorption other researchers have observed in previous studies:

• Boiled wild artichoke reduces postprandial glycemic and insulinemic responses in normal subjects by inhibiting the glucose absorption (100g of boiled plant on 50g of glucose in complete meal). Interestingly, this trick doesn't work in patients with type II diabetes (Nomikos. 2007)
• Significant increase in bile secretion and thus improved fat digestion.  1.92g of artichoke extract lead to increase of up to ~140% in a randomised placebo-controlled double-blind cross-over study published in Phytomedicine (Kirchhoff. 1994). 
• Beneficial improvements in endothelial function (-21% VCAM-1; - 17% ICAM-1 brachial +37% FMV) in hyperlipidemic patients with only 20ml of "self-made"* artichoke juice per day (*juiced by the researchers; Lupattelli. 2004).
• Provides "food" for probiotic Lactobacillus paracasei (LMGP22043) that have beneficial effects on faecal bacteria and biochemical parameters in human subjects (Valerio. 2011).
• Has UV protective effects, when applied to the hair (Fernandez. 2012) - not that important for your overall  health, but still quite telling, right?)
• 2x 200mg of ALE per day decrease total cholesterol and LDL and increase HDL in subjects with existing hypercholesterolaemia (Rondanelli. 2013)

I know that you'd probably love another 200 references to studies that support the beneficial health effects of artichoke and artichoke extracts, but you know what? I think that's enough for a preliminary conclusion.

Diabetes or Not-Diabetes - That's not just about the foods you eat, but also about what your body does with them: "Dietary Fructose vs. Endogenous Fructose Production: Is The Aldose Reductase Mediated Production of Fructose to Blame for Diabesity & NAFLD? Could Amla Help? " | more

Bottom line: With the existing evidence for its acute anti-hyperglycemic effects, its beneficial effects on lipid digestion and metabolism and reliable evidence from a 2005 study by Wittemer that the antioxidant caffeoylquinic acids and flavonoids are orally bioavailable in humans (Wittemer. 2005), it appears as if artichokes would make a a highly underrated, yet profoundly beneficial addition to everyone's diet.

With commercially prepared extracts, on the other hand, you do not just run the risk of buying not / incorrrectly standardized products without active ingredients, but could also be missing out on the actue anti-hypoglycemic effects, which are probably mediated by the fructan-content of the whole "fruit"; not the caffeoylquinic acids and flavonoids you can buy in capsule-, pill- or tablet-form (cf. Rumessen. 1990; the dosage of fructans that did the trick here was 20g!)

Reference:

• Barnes, J., Anderson, L.-A., Phillipson, J.-D. (Eds.), Herbal Medicines, Pharmaceutical Press, London 2007. 
• Betancor-Fernandez, A., P´ erez-G´ alvez, A., Sies, H., Stahl, W., Screening pharmaceutical preparations containing extracts of turmeric rhizome, artichoke leaf, devil’s claw root and gar lic or salmon oil for antioxidant capacity. J. Pharm. Pharma col. 2003,55, 981–986. 
• Englisch, W., Beckers, C., Unkauf, M., Ruepp, M. et al., Effi cacy of artichoke dry extract in patients with hyperlipopro teinemia. Arzneimittel-Forschung. 2000,50, E260–E265. 
• Fernandez, E., Martínez-Teipel, B., Armengol, R., Barba, C., & Coderch, L. Efficacy of antioxidants in human hair. Journal of Photochemistry and Photobiology B: Biology.  2012
• Holtmann, G., Adam, B., Haag, S., Collet, W. et al., Efficacy of artichoke leaf extract in the treatment of patients with functional dyspepsia: a six-week placebo-controlled, double blind, multicentre trial.Aliment. Pharmacol. Ther. 2003,18, 1099–1105.
• Jimenez-Escrig, A., Dragsted, L.-O., Daneshvar, B., Pulido, R. et al., In vitro antioxidant activities of edible artichoke (Cynara scolymusL.) and effect on biomarkers of antioxi dants in rats.J. Agric. Food Chem. 2003,51, 5540–5545.
• Kirchhoff, R., Beckers, C. H., Kirchhoff, G. M., Trinczek-Gärtner, H., Petrowicz, O., & Reimann, H. J. Increase in choleresis by means of artichoke extract. Phytomedicine. 1994, 1(2), 107-115.
• Lupattelli, G., Marchesi, S., Lombardini, R., Roscini, A. R., Trinca, F., Gemelli, F., ... & Mannarino, E. Artichoke juice improves endothelial function in hyperlipemia. Life sciences. 2004, 76(7), 775-782.
• Marakis, G., Walker, A. F., Middleton, R. W., Booth, J. C. L., Wright, J., & Pike, D. J. (2002). Artichoke leaf extract reduces mild dyspepsia in an open study. Phytomedicine, 9(8), 694-699.
• Menghini, L., Genovese, S., Epifano, F., Tirillini, B. et al., Antiproliferative, protective and antioxidant effects of arti choke, dandelion, turmeric and rosemary extracts and their formulation.Int. J. Immunopathol. Pharmacol. 2010,23, 601– 610. 
• Nomikos, T., Detopoulou, P., Fragopoulou, E., Pliakis, E., & Antonopoulou, S.. Boiled wild artichoke reduces postprandial glycemic and insulinemic responses in normal subjects but has no effect on metabolic syndrome patients. Nutrition Research. 2007, 27(12), 741-749.
• Root, H. F., & Baker, M. L. Inulin and artichokes in the treatment of diabetes. Archives of Internal Medicine. 1925, 36(1), 126.
• Rondanelli, M., Giacosa, A., Opizzi, A., Faliva, M. A., Sala, P., Perna, S., ... & Bombardelli, E. (2013). Beneficial effects of artichoke leaf extract supplementation on increasing HDL-cholesterol in subjects with primary mild hypercholesterolaemia: a double-blind, randomized, placebo-controlled trial. International Journal of Food Sciences and Nutrition, 64(1), 7-15.
• Rumessen, J. J., Bodé, S., Hamberg, O., & Gudmand-Høyer, E. Fructans of Jerusalem artichokes: intestinal transport, absorption, fermentation, and influence on blood glucose, insulin, and C-peptide responses in healthy subjects. The American journal of clinical nutrition. 1990, 52(4), 675-681.
• Valerio, F., et al. Role of the probiotic strain Lactobacillus paracasei LMGP22043 carried by artichokes in influencing faecal bacteria and biochemical parameters in human subjects. Journal of applied microbiology 2011, 111(1): 155-164.
• Wider, B., Pittler, M. H., Thompson-Coon, J., & Ernst, E. (2013). Artichoke leaf extract for treating hypercholesterolaemia. status and date: New search for studies and content updated (no change to conclusions), published in, (3).
• Wittemer, S. M., Ploch, M., Windeck, T., Müller, S. C., Drewelow, B., Derendorf, H., & Veit, M. Bioavailability and pharmacokinetics of caffeoylquinic acids and flavonoids after oral administration of Artichoke leaf extracts in humans. Phytomedicine. 2005, 12(1), 28-38.
• Zapolska-Downar, D., Zapolski-Downar, A., Naruszewicz, M., Siennicka, A. et al., Protective properties of artichoke (Cynara scolymus) against oxidative stress induced in cultured endothelial cells and monocytes .Life Sci.2002,71, 2897–2908. 

The Oiling of the Liver: The Good & Bad Short- & Long-Term Effects of Tocotrienol + Carotenoid Laden Red Palm Olein, Regular Palm-, Corn- and Refined Coconut Oil

I would not expect "red palm olein wonders", but more RPO and less corn oil in the American diet may at least buffer the liver disease burden in the US (the figure is based on data provided by the American Liver Foundation)

On Turesday, November 19, 2013, you've learned from a study by Subermaniam et al. about the "anti-rust" effects of coconut oil (if you missed that, you can catch up here), today, we are going back to Malaysia and the Universiti Kebangsaan Malaysia and the results of another team of researchers to learn about the effects the various oils have on the "oiling of the liver" (Dauqan. 2013).

I guess most of you will remember my previous comments about the critical role of the liver (and its health or disease) in the development of the metabolic syndrome (read it up). It is thus by no means irrelevant, whether the chronic ingestion of a certain type of oil will result in MDA levels of 92µmol/g or  27.3µmol/g.

Boring!? No, rather surprising!

If you think this sounds boring and are by no means surprised that the malondialdehyde levels of the liver samples the researchers harvested after 4 weeks were 27.3µmol/g, 92µmol/g, 54µmol/g, 47.4µmol/g and 72.6µmol/g for the control diet with mixed fats, red palm oloein (RPO), regular palm oil (PO), corn oil (CO) and the previously celebrated coconut oil (COC), respectively, I would suggest you have a closer look at the the "magic" that happened over the following 4 weeks of on 15% RPO, PO, CO and COC diets.

Figure 1: MDA levels (µmol/g) of liver tissue as a marker of lipid oxidation after four and eight weeks on control diet or control diet with 15% of red palm olein, palm oil, corn oil or coconout oil (Dauqan. 2013)

Well, you see, the way the effects of red palm olein came full circle after another months on the 15% RPO diet is hardly "boring", is it? The MDA levels, a relatively reliable indicator of local lipid oxidation, of the rodents on the 15% red palm olein diet is now, 4 weeks after peaking at 92µmol/g down to 25.2µmol/g, indicating that the level of lipid peroxidation in the livers of the RPO group is now significantly lower than that of any other group (43.4µmol/g, 50.1µmol/g and 48.3µmol/g for control, palm oil, corn oil and coconut oil).

Short term detriments, long term benefits!

I know it sounds more than awkward, but eventually every SuppVersity student should be aware of the fact that the extrapolation of long-term effects from short-term data is a 'risky' business. Unfortunately, even 'experts' often disregard this fundamental rule, when they formulate their recommendations on nutrition, supplementation and exercise.

Table 1: Carotenoid  and vitamin E composition (in %) of crude palm oil and red palm olein; the data is from a different study by Bonni & Choo who tested commercially available products (Bonni. 2000)

The statement, "Prefer coconut oil and avoid red palm olein!", for example would have been a reasonable dietary if we did not know about the turn-around in the second part of the study, when the beneficial effects of the saturated fat content of the coconut oil begin to fade and the absence of natural anti-oxidants in refined coconut oil begins to show its ugly face. At this point, the moderate amount of unsaturated fats in red palm olein (13% omega-6, 0% omega-3; see Bonnie. 2000), of which I am honestly not sure if it is the actual reason of the initial increase in lipid peroxidation (remember: corn oil has more PUFAs!), or whatever other underlying cause of the initial rise in inflammation is overriden by the accumulating amounts of vitamins E and carotenoids from the red palm olein, which rendered the liver of the oxidation-proof, or "rustless" if you will - similarly rustless as the hearts of the rogents in the previously cited study by Subermaniam et al. (learn more).

200g of palm fruits have the same amount of tocotrienols as 4kg of oats. Learn more "tocotrienol" and red palm oil facts in "Tocotrienols: What They Are, What They Do & How They Work + Why the RDA of Palm Olein is NOT 1xCup Per Day " | more

Bottom line: I would like to formulate two take home messages for today's SuppVersity article. Firstly, a theoretical one, which shall remind you of the fact that you can do more harm than good, if you (accidentally) terminate a study in a transitional state and formulate long-term dietary recommendations based on short-term observations, because the study at hand clearly indicates that some effects - in this case the antioxidant effects of the tocopherols, -trienols and carotenoids - take their time to become measurable. And seconfly a very practical one, which is eventually only a reminder of the existence of red palm oil (see article referenced on the right) - an excellent source of dietary antioxidants and probably your only chance to get your tocotrienols and high(er) amounts of some of the rarer carotenoids from regular foods.

References: 

• Bonnie, T. Y. P., & Choo, Y. M. (2000). Valuable minor constituents of commercial red palm olein: carotenoids, vitamin E, ubiquinones and sterols. Journal of Oil Palm Research, 12(1), 14-24.
• Dauqan, E., Abdullah, A., & Sani, H. A. (2013). LIPID PEROXIDATION IN RAT LIVER USING DIFFERENT VEGETABLE OILS. Malaysian Journal of Analytical Sciences, 17(1), 300-309.
• Valls, V., Goicoechea, M., Muniz, P., Saez, G. T., & Cabo, J. R. (2003). Effect of corn oil and vitamin E on the oxidative status of adipose tissues and liver in rat. Food Chemistry, 81(2), 281-286.

Rustless Hearts: Adding 15-20ml of Virgin Coconut Oil to Your Diet May Counter the Oxidative Stress From Partially Oxidized Fats and Keep Your Heart Rust-Free

Could a daily dose of virgin coconut oil really be all it takes to escape the #1 leading cause of death (CDC data) - despite French fries and co?

Originally I wanted to post the results of this study from the Universiti Kebangsaan Malaysia as a short news item in the Facebook News. Then I decided that it may actually be worth to allow you to have a look a the surprisingly pronounced effects the addition (not replacement!) of 3-4 tablespoons of virgin coconut oil had on the in vivo lipid oxidation levels of rodent hearts in the course of this 4 months study at the end of which the researchers did not simply measure the systemic, but the more significant local malondialdehyde (MDA) levels. With the direct analysis of the presence of lipid oxidation production in the heart being a more reliable indicator of whether or not the changes the researchers observed in the study at hand are physically relevant...

Ah, I don't want to give it all away. So let's rather take a look at Subermaniam et al.'s attempt to "to investigate the influence of virgin coconut oil on the malondialdehyde level in the heart tissue of rats fed with heated palm oil." (Subermaniam. 2013)

Palm oil is ubiquitous

I am not sure if you are aware of that, but the regular palm oil (not the red PO with the high carotene and tocotrienol content), with its saturated - unsaturated fatty acid ratio close to one, has become the most widely used "vegetable oil" worldwide. In fact, if the product label says "vegetable oil" and there is a significant amount of saturated fats in a product, it's likely that what you are about to eat contains palm oil, which is easy to process and, with its 1:1 ratio of saturated to unsaturated fats relatively stable.

Rejection points of various oils (Marikkar. 2007; Berger. 2005; Casai. 2010)

Cooking with Virgin Coconut Oil (VCO) - good or bad idea? The answer to this question is not as straight forward as you may think. On the one hand frying the "virgin" oil, will have it lose it's virginity, i.e. most of those molecules that are responsible for the beneficial health effects. On the other hand, a study by Marikkar et al. (2007) shows that these molecules act as a buffer, due to which VCO has a 30% higher rejection point (13h vs. 10h of frying at "only" 180°C; compare to the other oils in the table to the right) than regular coconut oil (CNO) and refined corn oil (CO). After those 13h the concentration of newly formed compounds (TPCs) that have higher polarity such as oxidized triglycerides, diacylglycerides and fatty acids is >25% and downright unhealthy.

Despite being less prone to oxidation, the way the oil is reheated and (ab-)used for deep frying by the food industry can cause changes in the fatty acids composition of palm oil that may have significant health consequences.

"Repeatedly heated oil undergoes changes in physical appearance and a series of chemical reactions such as oxidation, hydrolysis and polymerization that eventually alter the fatty acid composition . Therefore, when the degree of unsaturation in fatty acid is greater, it is more vulnerable to lipid peroxidation (Choe. 2007)." (Subermanian. 2013)

In mouse and man, the ingestion of this chemically altered oil has been found to increase the levels of ,alondialdehyde  (MDA), one of the major end products of lipid peroxidation which causes endothelial damage, vascular inflammation and cell membrane injury (USDA. 2007).

Virgin coconut oil to the rescue?

Studies by Harrison and Ng have shown that the increases in MDA levels in response to the ingestion of oxidated palm oil causes "oxidative stress" and increases in blood pressure that cannot be countered by the ingestion of common antioxidants such as vitamin C and E (Harrison. 2007). Now, Subermaniam et al. were interested, whether the same would be true for the sunsaponifiable components in virgin coconut oil.

SuppVersity Suggested Read: True or false - Eating tons of medium chain triglycerides (MCTs) will make you lean | learn the truth!

In previous studies, these molecules, which are lost when the milk is not extracted under controlled temperature, have been linked to a host of beneficial health effects, e.g.

• anti-inflammatory and anti-thrombotic properties,
• the ability to reduce the oxidation of LDL cholesterol, or
• beneficial effects on the immune factor and cytokine response to endotoxins,

of the increasingly popular medium-chain-triglyceride rich oil from Cocos Nucifera Linn - an oil of which Figure 1 tells you that it has a lower peroxide value than freshly extracted palm oil even after processing and storage.

In view of its already established health benefits, the assumption that virgin coconut oil can ameliorate the pro-oxidative effect of diets that were fortified with 15% pre-heated palm oil, when it is administered to rodents at a daily dose of 1.43 ml/kg of body weight/day by oral gavage does not appear to be too far-fetched.

Figure 1: Left - MDA level in heart tissue after 4 months of feeding with basal diet (control), five times heated palm oil (HPO), basal diet and VCO supplementation (VCO) and five times heated palm oil with VCO supplementation (HPO+VCO; left); right - baseline peroxide value (in mEQO2/kg) of the oils used in the study (Subermaniam. 2013)

The rats stayed on these regular palm oil, pre-heated palm oil, regular palm oil + VCO, pre-heated palm oil + VCO and an unmodified control diet for 4 months. Thereafter, the thirty two rats were sacrificed and their heart tissues were harvested in order to measure the level of lipid oxidation. The results? Well, you just have to look at Figure 1 to see that there was a significant (p < 0.05) decrease in MDA (and peroxide / data not shown) values in the rodents which received the supplemental coconut oil on top of their heated palm oil diets.

Bottom line: It is unquestionably impressive that the effects of what would have been ca. 15-20ml commercially available virgin coconut oil for a human being were so pronounced that the oxidative stability of the lipids in the cells of the rodents on the HPO + VCO ended up being virtually identical to that of the rodents which received the regular chow. I must still warn you not to expect any of the meanwhile literal "Coconut Miracles".

In view of the fact that the benefits of the 'VCO supplement' did not depend on the presence of a "junk food" diet, it is still obvious that the addition of one or another tablespoon of virgin coconut oil may be one of the 1001 pieces of your personal "healthy lifestyle" puzzle - along with a protein- and vegetable-rich whole foods diet, exercise and more than just an occasional night of good night's sleep, of course ;-)

References

• Berger KG. The use of palm oil in frying. Malaysian Palm Oil Promotion Council. 2005.
• Casal S, Malheiro R, Sendas A, Oliveira BP, Pereira JA. Olive oil stability under deep-frying conditions. Food Chem Toxicol. 2010 Oct;48(10):2972-9.
• Choe E, Min DB. Chemistry and reactions of deep-fat frying oils. Journal of Food Science. 2007; 72(5):R77-R86.
• Harrison DG, Gongora MC, Guzik TJ, Widder J. Oxidative stress and hypertension. Journal of the American Society of Hypertension. 2007; 1(1):30-44.
• Marikkar et al. Assessment of the stability ofvirgin coconut oil during deep-frying. Cord 2007; 23(1).
• Ng CY, Kamisah Y, Faizah O, Jubri Z, Qodriyah HM, Jaarin K. Involvement of inflammation and adverse vascular remodelling in the blood pressure raising effect of repeatedly heated palm oil in rats. Int J Vasc Med. 2012;2012:404025.
• Subermaniam K, et al. Virgin Coconut Oil (VCO) Decreases the Level of Malondialdehyde (MDA) in the Cardiac Tissue of Experimental Sprague-Dawley Rats Fed with Heated Palm Oil. Journal of Medical and Bioengineering. 2014; 3(2).
• World  Vegetable  &  Marine  oil  Consumption,  World  Statistics, USDA, 2007, pp. 10

Update on Antioxidants & Exercise - Neither Vitamin C Nor E Have ANY Effect on the Response to Intense Exercise.

Image 1: If you add some reactive oxygen species to this mitochondrium, this will trigger beneficial, (mito-)hormetic adaptations, that could be blunted by too many antioxidants.

As a diligent reader of the SuppVersity, you have probably been following my posts on antioxidants and their potentially negative effect on the adaptive (hormetic) response to the exercise induced formation of reactive oxygen specimen. Although, I still believe that the theory may have its merit - especially in metabolically deranged people, where the exercise induced ROS formation would initially have to overcome the low-grade chronic "background" stress - it appears that for healthy people, and "moderately trained young men" on an intense exercise protocol, in particular, the ingestion of reasonable amounts (<1g of vitamin C and <400IU of vitamin E) does not pose a problem. At least this is what the results of two relatively recent studies by scientists from Washington School of Medicine (Higashida. 2011) and researchers from universities in Denmark and France (Yfanti. 2011) would suggest.

The hormetic benefits of inflammation

According to the mitohormesis hypothesis, the beneficial effects of exercise on health, in general, and glucose metabolism, in particular, are at least partly mediated by an increase in reactive oxygen species, which triggers downstream "hormetic" adaptation processes which result in increased oxidative capacity and insulin sensitivity, as well as a reduction in total inflammation (cf. previous posts on the work of S. Schmeisser and M. Ristow from the Department of Human Nutrition at the University of Leipzig. If this theory held true, or let's be more specific, if this theory which is largely based on observations in metabollically derranged, i.e. obese and/or type II diabetic subjects, was applicable to healthy people and athletes, as well, this could mean that the multi-vitamin, the vitamin C pills, the alpha-tocopherol (vitamin E) and all the other little helpers you have been taking religiously to increase your exercise performance would actually have hampered, not promoted your muscle gains, fat loss and whatever else you may have had in mind, when you hit the gym, the road, the field, the court or the green ;-)

Figure 1: Neither the high-dose supplementation protocol in rodents (HED: Human Equivalent Dose for 80kg), nor the moderate dose protocol in humans did block any of the measured beneficial adaptations to exercise in the studies by Higashida (2011) and Yfanti. (2011), respectively.

Let me say this right away: As long as you have not been following the recommendations of dubious nutritional gurus and self-proclaimed fitness "experts" to take 10g+ of vitamin C and vitamin E supplements in the 3000IU+ range, the little vitamin pills and powders are probably not the reason that your biceps is not growing and your belly is just as fat as it was, when you began training.

Figure 2: Serum vitamin C and vitamin E levels (µmol/L) in 21 subjects before, at the beginning and after 12 weeks of 5x a week strenuous cycling exercise with and without supplemental vitamin C & E (adapted from Yfanti. 2011)

As you can see in figure 2, supplementation with 500mg of vitamin C and 400 IU of vitamin E (more on the protocols used in the studies in figure 1) before and during 12 weeks of strenuous bicycle exercise training with a frequency of 5 sessions per week (HIIT, HIT and stead state, cf. figure 6) did increase the concentration of antioxidants in the blood of the 21 healthy, physically active subjects (age 18-40years) of the Yfanti study, who had not participated in physical exercise more than twice a week before the experiment. Despite higher vitamin C and E plasma levels, and contrary to the research hypothesis of the scientists, who had expected that the anti-oxidant supplementation would blunt the adaptive response to the exercise protocol,

[...] the present study showed that combined supplementation with vitamins C and E before and during 12 weeks of supervised, strenuous bicycle exercise training of a frequency of 5 days/week had no effect on maximal oxygen consumption, maximal power output, workload at lactate threshold, glycogen content, and CS and β-HAD activity in muscle.

In other words, supplementing with "reasonable" amounts of vitamin C and vitamin E had absolutely NO EFFECT (!) on the exercise induced metabolic adaptations or performance increases - that does yet also imply that taking anti-oxidants is of little benefit as long as the minimal dietary requirements are met... and if you still insist to poor money down the literally rat hole, you may be interested to hear that (assuming that the results from Higashida's rat study translate to humans), even 10g of vitamin C and 3000IU of vitamin E a day probably would not really make a difference - as long as you train heavy enough.

Figure 4: Exercise induced changes in GLUT-4 expression (arbitrary units) and 2DG transport (µmol/ml/20min) in rats subjected to 8 weeks of high dose antioxidant supplementation and 6days/week swimming exercise in the last 3 weeks (data adapted fro Higashida. 2011)

Of particular interest in this context is the effect of "mega-dosing" anti-oxidants on the exercise induced increase in insulin sensitivity, which has been reported to be impaired in previous studies (Ristow. 2009). As the data in figure 3 shows, the increase in glucose transporter (GLUT4) expression is slightly greater in the non-supplemented rats, BUT neither this difference nor the difference in measured 2-Deoxy-D-glucose (2DG) transport reach statistical significance.

Figure 5: Exercise induced changes in MDA, SOD and PGC-1α in rats subjected to 8 weeks of high dose antioxidant supplementation and 6days/week swimming exercise in the last 3 weeks (data adapted fro Higashida. 2011)

Moreover, Higashida et al. found no statistically significant differences in the increases of malondialdehyde (MDA), superoxide dismutase (SOD1 & SOD2) or PGC-1α, a marker for the mitochondrial fatty acid oxidation, between the rats in the two groups (cf. figure 5).

Now, I a confused and don't know what to believe

So what does all that tell us? Well, we can now be relatively certain that supplementing with vitamin C and vitamin E is a waste of time and money for most of us. What we still cannot say for sure, though is why the Ristow study from 2009, which even made it to mainstream media news, found detrimental effects of supplementing with 1g of vitamin C and 400IU of vitamin E on the adaptive response to 4 weeks of 5days/week 20min steady state aerobic training + 45 minute circuit training + 20 min warm up + cool down (Ristow. 2009), while the Yfanti study, with 500mg of vitamin C and 400IU of vitamin E did not find any effects of supplementation...

Figure 6: Exercise protocol that was used in the Yfanti study.

...the only reasonable explanation I have is that the protocol in the Ristow study may not have been intense enough. Unfortunately there is no detailed information on what the subjects did in the course of the "circuit training", but if that was your usual sissy type walk from one machine to the next, chances are that the level of ROS that was induced by this "exercise" protocol was so low that it was completely blocked by the supplemental anti-oxidants. The "cycling protocol" in the Yfanti study, on the other hand, is pretty intense. If you look at the schedule in figure 6 you will concede that this is almost the way athletes (and maybe you) train.

All that being said, it appears that all is coming back to what I have been writing (and also saying on SHR) several times before: Controlled oxidation is likely to be beneficial. It's like the fire in the oven that keeps you warm - the one you carefully take care of, in order to prevent your whole house to catch fire... if you are a marathon runner, the latter can happen pretty quickly and you will need (tons of ;-) antioxidants and even that will probably not suffice. If you are the housewife on the treadmill, who walks at 5km/h for 20min two times a week, on the other hand, even a few milligrams of vitamin C and a few units of vitamin E will blunt the little oxidative "damage" that you do and your "efforts" to increase your insulin sensitivity or whatever your intentions may be will be sabotaged by your vitamin supplements.

1.3g of Grape-Seed Extract Could Protect You From Oxidative Damage, Viral Infections, Obesity and Insulin Resistance, Reduce Your Heart Rate and Blood Pressure and Increase Your Nitric Oxide Production by >25%

Image 1: Bought in bulk, grape-seed extract is actually reasonably cheap... and it does not even taste as awful as some other herb / seed extracts ;-)

After initially being hailed as the yet another anti-oxidant panaceum, grape-seed extract (GSE) has been displaced by newer, fancier "superfoods" from the headlines of the major health and wellness newscasters. Therefore, even you, as a highly self-educated student of the SuppVersity could have missed out on a handful of recently released studies which reported antiviral effects of GSE (Su. 2011) and confirmed its ameliorative effect on diet-induced obesity (Ohyama. 2011) and (high) fructose-induced insulin resistance (Meeprom. 2011). Moreover, a meta-analysis of nine controlled with more than 300 human subjects and daily doses ranging from 250mg to 2,000mg of GSE, which was published in the Journal of the American Dietetic Association (Feringa. 2011), found that ...

[b]ased on the currently available literature, grape seed extract appears to significantly lower systolic blood pressure and heart rate, with no effect on lipid or CRP levels.

These results suggest that we (at least some of) the beneficial health effects that have been observed in rodent studies actually translate to human beings - something  we cannot (yet?) say for some of the next generation "panacea" ;-) This is also important in view of the significance of the results GSE-administration had on exercise-induced oxidative stress in a more recent study by scientists from the universities of Konya and Dicle in Turkey (Belviranli. 2011), which was published in the latest issue of the British Journal of Nutrition.

The experiments were carried out with 64 adult male Sprague Dawley rats who were randomly assigned to one of the following six groups:

• sedentary control (C, n=10), 
• chronic exercise control (CEC, n=11), 
• acute exercise control (AEC, n=11), 
• GSE-supplemented control (GC, n=10), 
• GSE-supplemented chronic exercise (GCE, n=11), and 
• GSE-supplemented acute exercise (GAE, n=11)

The rats in the treatment groups received a standardized GSE extract containing 54% dimeric, 13% trimeric, 7% tetrameric and <5% monomeric proanthocyanidines and undisclosed amounts of cathechines and oligomeric proanthocyanidines, at a daily dose of 100mg/kg body weight in their drinking water for 6 weeks.

Image 2: Click here to learn how to calculate human equivalent doses (HED)

Rat to human equivalent dosage calculation: If you have already read my dissertation on how to calculate the so-called human-equivalent-dose (HED), you will probably already have whipped out your calculator and are just about to type "100mg times the K-value for rats, which is 6; divided by the K-value for humans, which is 37" ... and what does your calculator tell you? Correct! The HED of 100mg/kg GSE in rats is 16.33mg/kg - in other words, if you weigh 80kg you will have to take roughly 1,300mg of grape-seed extract per day to mimic the dosage that was used in the study.

The dosage, according to the scientists, was chosen because it had elicited beneficial anti-oxidant effects in previous studies on alloxan induced diabetes (El-Alfy. 2005) and age-related oxidative damage (Balu. 2006). And, as Belviranli et al. had suspected, it exhibited similar protective effects against the oxidative stress triggered by both chronic, 5x a week treadmill exercise at 25m/min for 45 minutes, as well as, acute running on the treadmill at 30m/min until exhaustion.

Figure 1: Effects of acute or chronic exercise and grape seed extract (GSE) supplementation on plasma malondialdehyde (MDA) levels (data calculated based on Belviranli. 2011).

As you can see in figure 1, administration of 100mg/kg grape-seed extract per day augmented the beneficial effect of 6 weeks of chronic exercise on muscle MDA levels (-37% vs. -18% in the control group) and ameliorated the acute +22% increase in MDA levels due to increased lipid peroxidation during exhaustive treadmill running.

Figure 2: Effects of acute or chronic exercise and grape seed extract (GSE) supplementation on plasma nitric oxide (NO) levels (data calculated based on Belviranli. 2011).

GSE supplementation also increased the expression of nitric oxide (NO in  plasma; on average +25%) in all animals (cf. figure 2). Moreover, GSE ameliorated the increase in xanthine oxidase and adenosine deaminase activities due to acute exercise and triggered an overall increase in antioxidant enzyme activities.

So, even if your favorite anti-aging and health (onilne-)magazine or vendor appears to have forgotten about grape-seed extract. For a physical culturist like you and me, it may yet well be worth to (re-)include the extract from the seeds of the fruits of Vitis vinifera, which are a particularly rich source of vitamin E, linoleic acid and, most importantly, oligomeric proanthocyanidins, into our supplement regimen. And if the current study does not convince you, it may help, if I remind you of the 2006 study by Kijima et al. who were able to show that GSE due to its anti-aromatase activity can suppress tumor growth in a breast cancer model (Kijima. 2006) ... ah, and before I forget: don't be stupid and buy over-priced caps. Use google and find yourself a source of bulk grape-seed extract - don't worry the taste is not all too bad ;-)

Transfats the Last Bastion of the "Bad Fats"!? Two New Studies Shed Some Light onto Their Impact on Your Health.

Image 1: The Meet the Fats campaign is part of the stultification... ah I mean educational program of the American Heart Association

Meanwhile, even mainstream dietitians are beginning to understand that fats, which have been a, if not THE staple energy source in human history are not the bad boys the anti-fat hysteria of the 1980s would make us believe. Even the American Heart Association begins to advocate the use of "healthy fats" as part of a "heart healthy diet" - unfortunately, the AHA guys still lump Sat (that is the obese guy in the left) Trans (that is the sleazy guy in green) together, although the evidence against poor Sat (who obviously represents all saturated fats) is less conclusive than that against Poly, his money-grubbing sister who would do everything for her sponsors from the corn-industry... well, be that as it may, today's charge is against Trans who is accused of arson, or whole body inflammation, to be precise ;-)

New evidence against Trans is provided by two teams of experts, one from Europe (Bendson. 2011) and the Middle East (Dhibi. 2011). In what I personally would consider battery, Nathalie T. Bendson and her colleagues from Denmark and France assigned 52 (formerly ;-) healthy women randomly to receive
either 15.7g partially hydrogenated soybean oil or control oil without any industrially produced  trans fatty acids (IP-TFA) on a daily basis. The results were not life-threatening, but certainly not desirable:

After 16 weeks, IP-TFA intake increased baseline-adjusted serum tumor necrosis factor (TNF) by 12% more in the IP-TFA group compared with controls. Plasma soluble TNF receptors 1 and 2 were also increased by IP-TFA.

With TNF-alpha's role in the modulation of endothelial and vascular smooth muscle cell function as well as endothelial cell-blood cell interaction and "the importance of such alterations for vascular dysfunction, the initiation and progression of atherosclerosis" (Kleinbongard. 2010), Bendson et al.'s asssumption that

the IP-TFA-associated increase in cardiovascular risk beyond the adverse effect explained by changes in blood lipids may be partly due to induction of systemic low-grade inflammation

is possibly correct. Nevertheless, the jury is still out on how bad TNF-alpha actually is, as its role in cardiovascular disease is actually quite ambiguous with the aforementioned low-grade inflammation on the one hand and its ability to protect your heart by ischemic conditioning on the other hand.

Figure 1: Trans fat content of fresh soy oil, oxidized soy oi and margarine (data based on Dhibi. 2011).

More comprehensive evidence comes from a rodent study by Dhibi et al. who fed 48 male Wistar rats one out of four experimental diets which were either high in fat and included 20% fresh soybean oil diet (FSO), 20% oxidized soybean oil diet (OSO) and 20% margarine (MG) or based on the standard chow (control) with a protein/carbohydrate/fat ratio of 17/62/4 for 4 weeks (Dhibi. 2011). The liver function of the rats, as evidenced by the elevated transaminase levels (ALT, AST) and the increases in alkaline phosphatase (ALP) and lactate dehydrogensase (LDH) in figure 2, took a major beating.

Figure 2: Relative changes in transaminases (ALT, AST), alkaline phosphatase (ALP) and lactate dehydrogensase (LDH) in rats after 4 weeks on diets containing 20% fresh soybean oil, oxidized soybean oil or margarine (data calculated based on Dhibi. 2011)

I suppose the sponsors of the American Heart Association won't like this observation, but it is as plain as the nose in your face that even the "transfat free, heart-healthy polyunsaturated soybean oil" led to statistically significant increases in alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels... what, ah... of course that is because the diet was high in fat - how could I forget that 20% fat is still way too much and humans, just like rats should eat a 62% carb 4% fat diet ... I guess that was enough sarcasm for one blogpost, so let's back to the facts, now.

Figure 3: Correlation  between  fatty  acid  isomers  in  the  diet  and  oxidative  stress
  parameters in rat’s liver and plasma hepato-specific enzymes (data based on Dhibi. 2011).

The changes in liver function were accompanied by profound reduction in antioxidant enzyme activity (SOD: superoxide dismutase; GPx: glutathione peroxidase; CAT: catalase) and increased accumulation of conjugated dienes (CD) and malondialdehyde (MDA), the respective correlations of which with the fatty acids isomers (trans fats from mono-unsaturated and poly-unsaturated fatty acids, as well as total transfat content) are plotted in figure 3.

Image 2: Rat liver histology.

Due to its scale (only two different transfat profiles, i.e. oxidized soybean oil and margarine) the study's statistical power is yet so small that we can only make a definite case against the total transfat content for decreases in catalase activity and oxidized polyunsaturated fatty acids for the accumulation of conjugated dienes. With correlations in the the >0.5 and <-0.5 range for many other suspects and crimes, I will yet leave it up to you, the jury, to decide, which members of the transfat family (I suppose the American Heart Associations Trans character must have a whole bunch of children, then - just like in every honorable mafia family ;-) are to be held responsible for which of these crimes against health, the ultimate result of which you see in the histological changes in the livers of the rats fed with oxidized soy oil (OS) and margarine (MG)... So, members of the Jury, on the Case of Trans Fatty Acid (and his mafia clan) vs. the Suppversity, what you say?

Rodent Study Suggests: Selenium, Nature's Neuronal Corrosion Inhibitor Could Protect the Brains of Hard Training Athletes from Oxidative Damage.

Image 1: Selenium is a naturally occurring mineral
involved in a host of metabolic processes.

Are you a hard training athlete? A weekend warrior? Marathon runner? Or just an an average fitness-enthusiast? Yes? Did you ever think about what an exhausting workout, let alone arduous marathon running may do to your brain? No? Then it may come as a surprise to you that other than regular moderate physical exercise, which has repeatedly been shown to exert beneficial effects on mental and physical development, intense exercise precipitates oxidative stress not only in the working muscle groups, but within your whole body - including your brain, where the exercise-induced increase in free-radicals may dramatically increase lipid oxidation (Goldfarb.1996; Kanter. 1998).

Based on observations with other antioxidants and the well-established involvement of selenium in the activation of the master-antioxidant glutathion, researchers from the Selcuk University in Konya, Turkey, hypothesized that supplementation with yet to be determined amounts of selenium might ameliorate the detrimental effects of arduous exercise (Akil. 2011). To verify their hypothesis, the Akil et al. subjected a group of 4-6 month old Sprague-Dawley rats to one out of four treatments for 4 weeks:

• group 1: unsupplemented sedentary control
• group 2: selenium supplemented, sedentary control
• group 3: swimming control (30 minutes in a closed glass-swimming pool; 50x50cm)
• group 4: selenium supplemented + swimming (same as group 3)

Both, the animals in group 2 and group 4 were supplemented with additional  0.6mg/kg of selenium selenite per day. For an 80kg adult human being the human equivalent dose of 0.098mg or 90mcg per kilogram of body weight would amount to 7.8mg of additional selenium per day, a dose, of which textbook knowledge tells us that it is way beyond the upper-limit of 0.8mg/day. Yet, for the rats, this supposedly toxic amount of selenium turned out to be quite beneficial.

For more on the beneficial effects high doses of selenium may have and a short discussion of toxicity issues, see my previous post on "NAC + Zinc + Selen = Silver Bullett Against Mercury Poisoning"

As the data in figure 1 shows, the non-supplemented arduously exercising rats (group 3) had by far the highest malondialdehyde (MDA is an accepted marker of unwanted oxidation) levels. On the other hand, the MDA levels of the supplemented group were reduced by 11%. Compared to the sedentary controls, which had identical (i.e. within the statistical margin) MDA levels, the malondialdehyde content of their brains was still elevated by 57%. While selenium supplementation may thus have ameliorated the increase in brain MDA levels, it was not able to completely protect the rat-brains from free-radical induced oxidation processes.

Figure 1: Malondealdehyde (MDA) and glutathione levels in rat brains after 30 minutes of exhaustive swimming exercise (data adapted from Akil. 2011)

Interestingly, in both, the supplemented, as well as the non-supplemented exercise groups brain glutathion levels (GSH) increased by 124% and 71%, respectively - probably to protect the brain from extensive oxidation. Under this assumption the selenium induced increase in glutathione levels, which lead to a 53% greater GSH increase in the brains of the rats in the selenium supplemented swimming group, would adequately explain the lower MDA levels of the high selenium group.

While it would have been nice to see a comparison of the effects of different doses and exercise protocols, the study at hand is just another hint a the importance of a mineral, that was believed to be toxic up to the late 1950. Consequently, this is neither the first, nor will it be the last time you read about this extraordinary mineral on the SuppVersity - stay tuned for more!

Iodine Induced Reduction in Hepatic Deiodinase Activity Leads to Hypothyrodism and the Accumulation of Liver Fat That May Eventually Pave the Way to Diabesity

While us Westerners think of goitre mostly as a result of iodine deficiency, the Chinese have learned by hard that the opposite is about as likely - goitre in response to iodine in the drinking water is a huge health problem in certain parts of the country (Zheng. 2000)

As colorful as the web may have become, it is still full of paradigmatic black-and-white thinking: The world is either black or white and if you browse the blogosphere, it would appear that iodine would certainly belong to the white part of our world. That in exactly those people who are often referred to as an example of the multitude of beneficial health effects, namely the Japanese, a high intake of iodine has repeatedly been shown to be associated with low thyroid function and even full-blown hypothyroidism, on the other hand, is something you will probably not learn from the tons of unreferenced stuff you'll find on the Internet about how good, if not essential it was for your health to take copious amounts of iodine everyday (about the same amount you would take if the nuclear powerplant next to you exploded to saturate and shut down your thyroid and prevent it from taking up the radioactive iodine).

The Ying and Yang of high and low iodine intake

A recently published rodent study from the Huazhong University of Science and Technology, the Binzhou Medical University and the Shen Zhen Center for Chronic Disease Control, in China (Xia. 2013) does now shed some light onto the underlying mechanisms of the well-known thyroid disrupting effects of the structural backbone of all mammalian thyroid hormones, iodine. While the whole spectrum of disorders of iodine excess includes hypothyroidism, hyperthyroidism, autoimmune thyroiditis,embryo toxicity, and depression of brain development (Guo. 2006; Rose. 2001; Roti. 2001; Yang. 2006) Yun Xia et al. are probably the first to investigate its hazardous effects of iodine excess on the liver.

To this end, the Chinese researchers supplemented rats on a standard diet containing a baseline level of 365μg/kg iodine with different doses of iodine in the form of potassium iodate (KIO3) in the drinking water for 3 months:

"In 2000, the Chinese Nutrition Society stated that the recommended nutrient intake (RNI) of iodine of adults is 150μg/day and the tolerable upper intake level (UL) is 1,000μg/day.
Conversely, intake of iodine at about sixfold of its RNI may induce injury. In addition, many excess iodine animal experimental data indicate that ten times the normal iodine intake in mice for about 3 months can cause damage. Moreover,the results of our previous experiment show that drinking 1.2 mg I/L iodine water for 1 month had no significant effect on serum lipid metabolism, while prolonged exposure for 3 months induced an increase of serum cholesterol." (Xia. 2013)

According to these results, the mice in the study were randomized to receiver either 0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/L iodine, corresponding to 0-, 1-, 2-, 4-, 8-, and 16-fold of the adequate/normal iodine intake for 3 months to explore the dose-dependent effect of iodine on hepatic steatosis. In the course of the trial, dood consumption, water consumption of each group, were recorded meticulously and the weight gain of each mouse was recorded daily.

Additionally, another 60 weaning female Balb/c mice were randomly assigned to six groups and given iodine at different levels (0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/ml) for 1 month just for
measuring the oxidative stress parameters in serum and liver.

Figure 1: Triglyceride content in liver and serum, as well as SREBP-1c and fatty acid syntethase (FAS) activity after 3 months on diets with additional iodine (Xia. 2013)

While neither food intake, nor water consumption or weight gain differed significantly between the groups (data not shown), a brief glance at the data in figure 1 should suffice to see that there was a dose-dependent increase in hepatic triglyceride levels (=fatty liver disease) that was accompanied by corresponding increases in serum triglyceride, when the liver was clogged up to the max - as it appears to be the case with 8x or 16x higher than normal levels in the diet (for humans that would thus be ~1.6g or 3.2g of potassium iodiate).

Figure 2: Total antioxidant capacity, glutathione peroxidase, SOD, and lipid peroxidation (MDA) after 1 and 3 months expressed relative to untreated control (Xia. 2013)

The fatty acid accumulation in the liver was accompanied by profound changes in total antioxidant and SOD and glutathione status, as well as significant increases in lipid oxidation (as indicated by the +61% and +85% increase in MDA in the groups with the highest intake of supplemental iodine). Contrary to the commonly propagated myth that tons of supplemental iodine would increase the thyroid function these changes were accompanied by profound decreases in D1 deiodinase activity and correspondingly decreased conversion of T4 to T3 (see figure 3).

Figure 3: Changes in thyroid hormone and deiodinase levels; expressed. rel. to control (Xia. 2013)

It should thus not surprise you, that the levels of TSH and T4 in the rodents increased, while those of T3 decreased (no conversion = hypothyroism, no matter how much T4 you got floating around).

Low D1 => Low T3 => fatty liver disease

In fact, the reduced local conversion of T4 to T3, is also behind the accumulation of triglycerides in the liver and blood of the animals, as the

"[r]educed plasma T3 level resulted in the upregulation of SREBP-1c mRNA and FAS mRNA that ultimately led to the accumulation of triglycerides in the liver. [...] Evident hepatic steatosis was observed in mice challenged with 2.4 and 4.8 mg I/L iodine in drinking water. " (Xia. 2013)

As a SuppVersity student you know about the downstream effects, but I guess it makes sense to reiterate them for the newbies: Since the liver plays a, if not the pivotal role in systemic lipid homeostasis the reduced oxidation of triglycerides and the increased storage will sooner or later lead to an increased secretion of triglyceride-rich lipoprotein (VLDL) as a compensatory response by which the liver will desperately try to spread the lipid burdon to other organs and tissues. Overwhelmed with the sudden onslaught of triglyceride laden VLDL particles which are easily oxidized during their voyage through your blood stream, this opens the door to a narrowing of the arteries, cardiovascular disease and stroke.

---

For the majority of you, overtraining and undereating is probably a much greater threat, when it comes to hypothyrodism (learn more about "self-inflicted hypothyrodism"). However, contrary to excess iodine intake that will not clog up your liver and arteries and eventually cause heart disease and stroke.

Bottom line: If we assume based on the available epidemiological data that the general mechanism was identical in human beings, the ingestion of large amounts of iodine which are often touted as a remedy to all sorts of metabolic syndroms may in fact exert the exact opposite effects.

Yet, although I would be cautious about extrapolating the exact cut-off levels, it appears that dietary intakes in the 800µg range and thus 4-6x more than the RDA can still be considered relatively save. So if you are neither taking high dose supplements or living on tons of seaweed, this is probably not much of a concern for most of you. In addition it would warrant investigation if / to which extent the addition of extra selenium would ameliorate these effects. After all, the latter has been shown to have protective effects against iodine intoxication in the very same rodent model in a 2006 study by Xu et al. (Xu. 2006).

References:

• Guo H, Yang X et al. Effect of selenium on thyroid hormone metabolism in filial cerebrum of mice with excessive iodine exposure. Biol Trace Elem Res. 2006; 113:281–295. 
• Rose NR, Bonita R et al. Iodine: an environmental trigger of thyroiditis. Autoimmun Rev. 2002;  1:97–103.
• Roti E, Uberti ED. Iodine excess and hyperthyroidism. Thyroid. 2001;11:493–500.
• Xia Y, Qu W, Zhao LN, Han H, Yang XF, Sun XF, Hao LP, Xu J. Iodine Excess Induces Hepatic Steatosis Through Disturbance of Thyroid Hormone Metabolism Involving Oxidative Stress in BaLB/c Mice. Biol Trace Elem Res. 2013 May 28. 
• Xu, J, Yang, XF., Guo, HL, Hou, XH Liu, LG, & Sun, XF. Selenium supplement alleviated the toxic effects of excessive iodine in mice. Biological trace element research; 2006 111(1-3), 229-238. 
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