ALA, Berberine, Metformin, Resveratrol, AICAR & Co - Are AMPK Mimetics & Activators Good or Bad for Athletes?

Unless you're planning to just sit, instead of cycle on your spinning bike, it is by no means sure if your performance well benefit or maybe even suffer from the use of AMPK mimetics and activators.

Recently someone asked me on Facebook, whether AMPK activators like Lipoic acid (ALA), Berberine, Metformin, AICAR & Co wouldn't make excellent performance boosters. I pondered that question for some time and said: "If you are about to compete in a highly glycolytic sport, the opposite is probably the case."

There's little question that supplements like lipoic acid are useful if you are an overweight type II diabetic. But let's be honest: How many of you fall into this category? As healthy, active individuals or even athletes, on the other hand, you should be aware that the ability of these agents to increase the glucose uptake and block the glyconeogenic pathways in the liver may easily make you run out of fuel during anaerobic activities like lifting or sprinting.

Learn more about hormesis and how antioxidants can also impair your gains

Is Vitamin E Good for the Sedentary Slob, Only?

Even Ice-Baths Impair the Adapt. Process

Vit C+E Impair Muscle Gains in Older Men

C+E Useless or Detrimental for Healthy People

Vitamin C and Glucose Management?

Antiox. & Health Benefits Don't Correlate

This does not negate the fact that AMPK activators, by their ability to increase the use of free fatty acids as a substrate, may be of interest to endurance runners or athletes competing in other sports, where the lion's share of the energy they use during their workouts and competitions are carboxylic acids with a long aliphatic tail (chain), i.e. fatty acids.

Against that backround it is hardly surprising that the few pertinent studies that exist are - at least in parts - contradictory. Shortly before the last Olympic Games in Beijing, for example, a study was published that showed that the research chemical and AMPK activator AICAR (5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide) increased the running capacity of mice without any training. But let's be honest: Do you think athletes would be looking for agents that work without training... well, obviously they would, but AICAR - as potent as it may be - will never replace the blood, sweat and tears athletes have to invest to be successful. That's for sure.

Which AMPK activators are actually prohibited by the WADA? The WADA list of prohibited substances lists only "AMP-activated protein kinase (AMPK), e.g. AICAR; and Peroxisome Proliferator Activated Receptor δ (PPARδ) agonists e.g. GW 1516" which is pretty unspecific and leaves me questioning whether other natural AMPK activators like ALA, berberine, chlorogenic acid or the most widely used one, i.e. metformin, would be illegal, too.

Nevertheless, the observation Narkar et al. (2008) made was enough for the World Anti-Doping Agency (WADA) to include certain AMPK activators in the list of forbidden drugs - for all, not just endurance sports, obviously.

Table 1: Adenosine monophosphate-activated kinase activators and their impact on exercise capacity (Niederberger. 2015)

Actual experimental evidence of performance enhancing effects exists for several natural and synthetic AMPK mimetics and activators (see Table 1). If you look closely, however, you will notice that all those "enhacnements" and "increases" have been in rodent models and/or non-athletes.

What does the latest review say? As usual, the special needs of Olympic-lifters, bodybuilders, sprinters and all other athletes who are competing in anaerobic sports are ignored by the authors of the latest and - as far as I know - first review of the impact of the activation of AMPK on sports performance.

It's the increase in the total time and endurance as well as VO2 in a injection only (no training) rodent study observed by Narkar et al. in 2008 that is behind all the hype around AICAR as a "potent doping agent". I wonder if the athlete who use is even know that the mice in the study didn't even train. Whether the effect is additive is thus highly questionable.

In spite of their unfortunate ignorance of sports-specific differences, Niederberger et al. (2015) produce a neat overview of the available research on AMP mimetics like AICAR, pharmacological drugs like metformin, salycilic acid, thiazolidinediones, Phenobarbital and Telmisartan, and natural AMPK activators like green tea, capsaicin, resvertrol and co. Of these, none has been tested in athletes, though, even the applauded AICAR helps only in theory (!). Unlike Niederberger's review suggests, the performance enhancing effects in studies like (Hayashi. 1998; Cuthbertson. 2007; Narkar. 2008) were after all observed in the absence of baseline training and are thus not representative of what would happen in athletes who won't be dumb enough to believe that they don't even have to train if they are abusing AICAR.

The lack of relevant evidence for performance benefits in athletes that would be induced by AMPK mimetics, as well as the existing evidence that AMPK promoters like resveratrol, which don't target AMPK primarily, but must be thought of as potent antioxidants instead, entail the risk of anti-hormetic effects (e.g. the attenuation of the positive effects of endurance exercise on inflammatory and oxidative stress markers in aged men in response to 250mg resveratrol day in Olesen et al.'s 2014 study) put a huge "?" behind the actual usefulness of AMPK mimetics and promoters as athletic performance enhancers..

In the absence of experimental evidence from both rodent and human studies that involve AMPK activators and anaerobic exercise, we have to use our brains to find out whether sprinters, bodybuilders, or weight lifters and athletes competing in team sports that have both an aerobic and an anaerobic component would benefit as well. In this case the extensive research on alpha lipoic acid (ALA) can help us, but we should not forget that the effects may differ from one agent to the other.

Due to the previously mentioned potentially negative effect on blood glucose in insulin sensitive individuals that is mediated primarily by increases in whole body glucose oxidation, increased glycolysis (wasting of the glycogen reserves| Barnes. 2004) and a reduced ability to produce new glucose "on demand" (via gluconeogenesis, which is AMPKs main of glucose control according to Zhang et al. 2009), athletes competing in anaerobic sports may in fact run the risk of running low on blood sugar and thus compromising their performance and/or being even more reliant on sugary high carbohydrate beverage.

In insulin sensitive muscle cells ALA reduces the rate of glycogen synthesis (Dicter. 2002). This should remind you of this simple truth: What's good for your obese neighbor, ain't necessarily good for you. Plus: ALA ain't the only supplement with different, often opposite effects in lean vs. obese.

What's good for the obese is rarely good for athletes: The reduced protein synthesis (Figure 1) is only one of several undesirable side effects of high doses of ALA. One that people usually won't even believe exists is an impairment of glycogen synthesis in insulin sensitive skeletal muscle. While ALA is famous for partly restoring the whole body (including body fat) glucose uptake in insulin resistant individuals, studies like the one by Dicter et al. (2002) indicate that it will reduce the insulin-induced glycogen synthesis if the muscle in question is not insulin resistant, but sensitive. That's an effect that may occur only at higher dosages of ALA (and other potent AMPK activators), but still one that no athlete can ignore.

If you don't care about blood glucose, you may be intrigued to hear that AMPK will not act on your glucose metabolism, alone. Increasing levels of AMPK will also suppress skeletal muscle protein synthesis (Figure 1), which is a side effect that's probably even worse than the remote risk of hypoglycemia, specifically in athletes competing in anaerobic sports.

Figure 1: Changes in p-AMPK and nutrient-induced protein synthesis in myotubes from the EDL muscle (Saha. 2010).

Now, some of you may argue that I personally wrote in an older article in the Intermittent Fasting Series that the rise in AMPK due to exercise would not be a problem.

If you'd read that article carefully, though, you'd also know that this is because exercise triggers the release of a specific form of AMPK that's different from the one that's released during fasting and in response to regular AMPK activators. It is thus not unlikely that high(er) intakes of ALA as they would probably be abused by athletes, who (falsely) believe they'd benefit from it, can impair the protein synthesis to a similar extent as it was observed by Saha et al. in their 2010 study in rodent EDL muscles.

Furthermore animal studies show that chronic administration of albeit very high doses of ALA, equivalent to ~5g/day for a human being, will actually trigger significant reductions in lean mass (Shen. 2005) - something almost every athlete who's competing in anaerobic sports will want to avoid.

The answer to the question in the headline is - as so often: "It depends!" If you are an endurance athlete, the acute, yet not the chronic consumption of the AMPK mimetics (=acts just like) like AICAR and maybe some of the less potent AMPK activators could improve your endurance. Without studies where the rodents (or even better men and women) are actually trained, even this assumption is speculative.

Figure 2: While the last word has not been spoken, yet the impaired adaptive response to stressors in older subjects supplementing w/ 250mg/day resveratrol Olsen et al. observed in 2014 is further evidence that the chronic consumption of potent antioxidants (which happen to be AMPK promoters in this and other cases like ALA) must not be recommended unconditionally for athletes based on the available evidence.

If, on the other hand, you're competing in sports where anaerobic performance, i.e. power, speed and other parameters that will critically depend on the availability of glucose, you will probably see no beneficial and, in the worst case, detrimental effects.

These detrimental effects could also occur in response to the chronic ingestion of AMPK promoters like lipoic acid due to their potentially negative effect on protein synthesis and glycogen repletion, as well as in response to the chronic use of potent anti-oxidants for which evidence exists that they impair the hormetic response to exercise and may thus be detrimental for athletes competing in both anaerobic and aerobic sports.

If you take small amounts of berberine, ALA, resveratrol, or other agents that have been shown to exert their health benefits via AMPK, though, it is very unlikely that the previously discussed unwanted side effects surface (don't expect direct ergogenic effects, though). Moderation is - as so often - the key to perfect happiness | Comment on FB!

References:

• Barnes, Brian R., et al. "The 5′-AMP-activated protein kinase γ3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle." Journal of Biological Chemistry 279.37 (2004): 38441-38447.
• Cuthbertson, Daniel J., et al. "5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men." Diabetes 56.8 (2007): 2078-2084.
• Hayashi, Tatsuya, et al. "Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport." Diabetes 47.8 (1998): 1369-1373.
• Narkar, Vihang A., et al. "AMPK and PPARδ agonists are exercise mimetics." Cell 134.3 (2008): 405-415.
• Niederberger, Ellen, et al. "Activation of AMPK and its Impact on Exercise Capacity." Sports Medicine (2015): 1-13.
• Olesen, Jesper, et al. "Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men." The Journal of physiology 592.8 (2014): 1873-1886.
• Saha, Asish K., et al. "Downregulation of AMPK accompanies leucine-and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle." Diabetes 59.10 (2010): 2426-2434.
• Shen, Q. W., et al. "Effect of dietary α-lipoic acid on growth, body composition, muscle pH, and AMP-activated protein kinase phosphorylation in mice." Journal of animal science 83.11 (2005): 2611-2617.
• Zhang, Bei B., Gaochao Zhou, and Cai Li. "AMPK: an emerging drug target for diabetes and the metabolic syndrome." Cell metabolism 9.5 (2009): 407-416.

Fighting to Stay Lean? These 20+ Anti-Obesity Agents Have the Potential to Inhibit Fat Gain Right at the Cellular Level

No, none of the 20 agents in the list below is going to do the work for you, but they could help you "conserve" the results, keep you lean on a bulk and/or avoid the hazardous Yoyo effect when you go off a die.

It's actually normal that the introduction is the last part of an article I write. What's special about today's SuppVersity article is thus not that I write the introduction at the end, but that I did not really know what I would be writing here, when I set out to compile the unsorted (but not chaotic) list of potential anti-obesity agents below. All of them act by pathway(s) you as a SuppVersity reader will have read about before, most prominently AMPK, and the peroxisome proliferator receptors (PPARs), of which the blockade of the obesogenic PPAR-gamma pathway, which is the main working principle of CLA turned out to be the go-to explanation for the ability of these agents to block both the differentiation of adipocytes and the storage of triglycerides in existing fat cells.

20 more or less proven anti-obesity agents for the weekend

As you are about to see, the list, which was never intended to be complete, got pretty and I guess I could add a couple of additional items, if I spent more time digging. In order not to steal your and waste more of my precious time on this sunny (finally!) Sunday, I did yet decide to call it a day, when I hit the 20-items mark. Now it's up to you to invest some of your sunny Sunday time, to read up on the details. 

• On a side note: The "holy" vitamin D does the exact opposite, if you incubate preadipocytes with 25(OH)D(3) this will lead to a significant increase in the active 1,25(OH)(2)D(3) and enhanced adipogenesis in primary mouse. Reason enough for a group of Thai researchers to conclcude that "vitamin D status may [actually] regulate human adipose tissue growth and remodeling." (Nimitphong . 2012)
  Vitamin A - Retinoic acid upregulates the expression of the adipogenesis inhibitors Pref-1, Sox9, and Kruppel-like factor 2 (KLF2) to "suppress adipogenesis in vivo and that the activity significantly contributes to the ability of the hormone to counteract diet-induced obesity." (Berry. 2012) Previous studies have also shown that all-trans-retionic acid directly increases the activity of PPARbeta/delta and so that Berry & Noy conclude "RA may be a uniquely efficacious agent in the therapy and prevention of the metabolic syndrome." (Berry. 2009) Similar results have been reported and conclusions have been drawn by Brun et al. and Sagara et al. (Brun. 2012; Sagara. 2013). Finally, Hisada et al report that - just like testosterone (learn more) - retinoic acid ensures that mesenchymal stem cells (MSCs) become osteoblasts (bone precursor cells), not fat cells (Hisada. 2013).

• Bromocriptine - If you do know it at all, then probably for it's ability to decrease the "milk hormone" prolaction. If you take a look at the broad spectrum of physiological effects of prolactin, the effect it has on the mammalian mammary gland is really negligible. A recent study from the Department of Biotechnology at the Daegu University in The Republic of Korea does now suggest that the inhibition of adipogenesis (formation of new fat cells) and lipogenesis (storage of lipids in existing fat cells) via decreased expressions of the adipogenic activators Pparα, Pparγ, and Cebpα, as well as major lipogenic target genes, including Me1, Acc1, 6Pgd, Fasn, and Prkaa1 is one of these "auxiliary functions" (Mukherjee. 2013)

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  EC also boosts erectile performance and testosterone (learn more)

  Ecklonia cava (EC) - or rather the dioxinodehydroeckol (DHE) molecules that are contained in this type of brown seaweed "exert[s] its anti-adipogenic effect on adipocyte differentiation through the activation and modulation of the AMPK signaling pathway" (Kim. 2010a). As a SuppVersity reader, you will be aware that this effect has been confirmed in in-vivo studies, later on (learn more).
  
  What's probably Interestingly DHE is not the only anti-adipogenic agent in brown sea algae, Fucoidan, a sulfated polysaccharide from brown seaweeds has likewise been reported to affect the development of adipocytes. In 2010, Kim et al. were able to show that it targets the MAPK kinase pathway by inhibiting the the expression of both early CCAAT-enhancer-binding proteins alpha (C/EBPalpha) and peroxisome proliferator-activated receptors gamma (PPARgamma), as well as the late activating protein 2 (aP2) adipogenic transcription factors (Kim. 2010b).

• Curcumin - While you my get the impression there was nothing curcumin cannot do (learn more), I am not whether the anti-PPAR gamma effects of curcumin are a result of it's anti-inflammatory effects or not... be that as it may, Lee et al. have demonstrated in 2009 already that the stimulatory effect curcumin exerts on the AMPK expression of adipocytes results in a down-regulation of PPAR-gamma in 3T3-L1 adipocytes (Lee. 2009).

• Resveratrol - Similar popularity, similar "cures it all" status and similar effects on AMPK and downstream PPAR-gamma expression in 3T3-L1 adipocytes... actually I would not need another bulletin point for resveratrol which acts by the exact same pathway(s) s curcumin to inhibit fat cell differentiation (Chen. 2011)

• 

  Creatine RT by Athletic Edge Nutrition; contains a cousin of ASL and is supposed to be another "super creatine" -  True or False? The 2011 SuppVersity article has the answer (read it!).

  Artemisia sacrorum Ledeb. (ASL) - Extracts from the small shrub have been used in Oriental Medicine for centuries, in 2011 Yuan et al. were able to show that ASL "down-regulate[s] the adipogenesis-related gene expression of the sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, such as fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1) and glycerol-3-phosphate acyltransferase (GPAT) in a concentration-dependent manner" (Yuan. 2011) The effects are meediated by a reduced expression of the peroxisome proliferator-activated receptor γ (PPARγ) and of the CCAAT/enhancer binding protein-α (C/EBPα), both of which are key transcription factors in adipogenesis.
  
  With the concomitant reduction in adipocyte fatty acid binding protein (aP2) gene expression, ASL is another potential anti-obesity agent of which Yuan et al. propose that it works its  anti-adipogenic magic via AMPK activation. In view of the fact that the same is true for the fat accumulation in human liver cells, it could serve a viable tool "in the prevention of serious diseases such as fatty liver and type-2 diabetic mellitus" (Yuan. 2010). Related increases in fatty acid oxidation have been observed in a rodent study by Hong later in 2009 with another variety of Aertemisia, namely Artemesia Capillaris (Hong. 2010). The human equivalent dosage in this trial wast 8mg/kg of the ethyl acetate fraction of the shrub.

• Phosphorylated glucosamine - While you will probably remember that large doses of regular glucosamine have been associated with insulin resistance (see previous installment of "True Or False"), it's phosphorylated variety glucosamine-6-phosphat (PGlc), Kong et al. synthesized using methanesulfonic acid, phosphorus pentoxide (P(2)O(5)), NH(2)NH(2) and DMF "significantly reduced lipid accumulation during adipocyte differentiation and induced down-regulation of peroxisome proliferator-activated receptor-gamma, sterol regulatory element binding protein 1 and CCAAT/enhancer binding protein-alpha in a dose-dependent manner." (Kong. 2010)
  

  

  Phosphorylated glucosamine works (like most of the anti-obesity agents, including the well-known conjugated linoleic acid by reducing the expression of PPAR-gamma (left). It's dose-dependent effects are yet not restricted to the peroxisome proliferator receptor, but affect the pro-adipogenic genes C/EBP-alpha and SREBP1, as well (right; Kong. 2010)

  What's also worth mentioning is that the in-vitro study from the Marine Bioprocess Research Center at the Pukyong National University in South Korea also revealed that PGcl also hampered the maturation of pre-adipocytes by down-regulating adipocyte-specific gene promoters such as adipocyte fatty acid binding protein, fatty acid synthase, lipoprotein lipase and leptin. In conjunction "[t]hese results suggest that the inhibitory effect of PGlc on adipocyte differentiation might be mediated through the down-regulation of adipogenic transcription factors, such as peroxisome proliferator-activated receptor-gamma, sterol regulatory element binding protein 1 and CCAAT/enhancer binding protein-alpha, which are related to the downstream adipocyte-specific gene promoters" (Kong. 2010) 

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  Add. reads: "Temporary +100kcal/Day Cold Thermogenesis Response W/ Exotic Ginger Extract" (more) "250-1000mg of Freeze-Dried Ginger Reduce Visceral Fat Even When Rodents Are Fed an Obesogenic High Fat Diet" (more).

  6-gingerol (6G) - The active ingredient in ginger has just been shown to block the obesity effects of the anti-diabetes med rosiglitazone (Tzeng. 2013). It does so by blocking the PPAR-gamma mediated effects of the "store the superfluous energy as body fat"-drug and was thus able to suppress the oil droplet accumulation and reduce the sizes of the droplets in the course rosiglitazone(RSG)-induced adipocyte differentiation in 3T3-L1 cells. Since it also blunted the increased levels of mRNA and protein in adipocyte-specific fatty acid binding protein 4 and fatty acid synthase induced by RGZ, it can be expected that 6G will not only inhibit the accrual of new, but also the (re-)filling of existing fat cells. 

• Piperine and capsaicin - In view of the fact that piperine is a "quasi-cousins" of 6-gingerol, it is actually not really surprising that it shares similar effects on the expression of PPAR-gamma (Park. 2012). It is therefore not surprising that the third member of this spicy triumvirate, i.e. capsaicin, shares the exact same PPAR-gamma reducing effects (Joo. 2010).

• Berberin - Contrary to many other items on the list, berberin's anti-PPAR-gamma effects are actually pretty well-known. There is ample evidence from in-vitro (Huang. 2006; Liu. 2009) and in-vivo (Lee. 2006) evidence that it blunts fat gain by increasing the catabolism of high energy intermediates, upregulating AMPK, modulating the expression of the GATA-2 and 3 gene and reducing the expression of (you guessed it) PPAR-gamma (Hu. 2009).

  

  Table 1: Berberine content of various commercially available supplements (Brown 2008)

  Berberine has also been shown to improve endothelial function in man (Wang. 2009) and promote the "longevity and mitochondrial health gene" SIRT1 in obesity ridden, insulin resistant skeletal muscle (Gomes. 2012).

• Ginsenosides (spec. ginsenoside Rg3) - Just like ginereol (see above) ginsenoside Rg3 has been shown to block the adipogenic effects of the anditiabetic drug rosiglitazone via an AMPK/PPAR-gamma dependent pathway (Hwang. 2009). It may be worth mentioning that at least the effect triglyceride storage was not dose-dependent. Once  a threshold amount of 40µM was reached, the adipocytes that were incubated with Rg3 did not "lose" any additional triglycerides, when the dosage was increased to 80µM.

• On a side note: Although promoted in the same health and longevity circles as CAPE, the hailed "telomerase lengthener" Astraglaus is a PPAR-gamma promoter and will thus "enhance the accumulation of lipid drops, and increase the terminal differentiation of preadipocytes" (Liu. 2007)
  Caffeic acid phenethyl ester (CAPE) - You've heard about the anti-inflammatory, muscle protective ability of this compound from bee propolis only recently (go back). In addition to being a potent anti-inflammatory, the natural phenolic compound that's also found in a variety of plants, has also been found to block the conversion of mouse fibroblasts into fat cells (Juman. 2010). As for most of the other agents the effects of CAPE appear to be mediated by a reduction inperoxisome proliferator-activated receptor (PPAR) gamma and CCAAT/enhancer-binding protein (C/EBPalpha) and concomittant reduction isn fatty acid synthetase and the expression of adipocyte-specific fatty acid binding protein (aP2). 

• Lysimachia foenum-graecum (LFE) - LFE is a Chinese herb and well-known anti-inflammatory from Oriental Medicine. The anti-obesity effect of L. foenum-graecum extract was first discovered by Seo et al., when they simply screened a whole host of potential natural agents for their anti-adipogenic effects. In 2011 the researchers found that "LFE blocked the differentiation of 3T3-L1 preadipocyte in a dose-dependent manner with an IC50 of 2.5 μg/ml". The underlying mechanism which has also been observed in an in-vivo rodent study with 100 mg/kg/day, are - how else could it be - mediated by the inhibition of PPARγ and C/EBPα expression.

  

  Effects of the administration of an lysimachia foenum-graecum ethanol extract on lipid and glucose metabolism and adipokine signalling in mice on an obesogenic diet (Seo. 2011)

  Moreover, LFE stimulated fatty acid oxidation in an AMPK-dependent manner, greatly improved serum levels of obesity-related biomarkers such as glucose, triglycerides, and adipocytokines leptin, adiponectin, and resistin and lead to an effective decrease in total body weight gain in mice who received 30, 100, and 300 mg/kg/day of an Lysimachia foenum-graecum ethanol extract (50:6; LFE) in addition to their obesogenic high fat diet (see figure above). The mice in the HFD + LFE group did simply have lower body weights, they also had a reduced amount of adipose tissues especially within the metabolically active and highly unhealthy abdominal subcutaneous, epididymal, and perirenal adipose tissue.

• 

  Photos of the lean (A and D), HFD-fed (B and E) and HFD-fed + SRLE supplemented (C and F) mice in the Thounaojam study (2011).

  Sida rhomboidea. Roxb leaf extract (SRLE) - SRLE does only sound like the stuff many supplement companies used after the ban of mua huang (natural source of ephedrine). It is however a different variety of Sida (Batyάlaka, Sida cordifolia)... well, at least it is from the same family which lacks the CNS stimulating activity of mua huang. With its ability to prevent high fat diet (HFD) induced visceral adiposity by down-regulation of PPARγ2 and leptin gene expression it could in fact work synergistically with ephedrine, though. After all the HED of the 24% w/w water extract Thounaojam et al. used to prevent the obesogenic effects of a hypercaloric high fat diet in their rodent study amounts to no more than ~40mg/kg and since SRLE has been shown to be non-toxic up to 3g/kg (in mice; HED ~240mg/kg) it would be interesting to see studies that probe whether it works in humans (Thounaojam. 2011).

• SH21B is an anti-obesity composition composed of seven herbs: Scutellaria baicalensis Georgi, Prunus armeniaca Maxim, Ephedra sinica Stapf, Acorus gramineus Soland, Typha orientalis Presl, Polygala tenuifolia Willd and Nelumbo nucifera Gaertner (active ingredients; see figure below) that has been used for the treatment of obesity in traditional medical clinics in Korea and has recently been shown to decrease the expression of major transcription factors of the adipogenesis pathway and result in the down-regulation of lipid metabolizing enzymes involved in the transport, uptake and synthesis of lipids - unfortunatedly, only in vitro (Lee. 2009)

  

  Effects of SH21B on fat droplet formation in 3T3-L1 cells (top) and size of adipocytes in adipose tissue. (bottom), as well as active ingredients in SH21B (based on Lee. 2009)

  As you can see in the stains from the adipose tissue of the above, the effects are clearly mediated by both an inhibition of the maturation of preadipocytes (top) and the inhibition of fat storage... now you tell me the world needs "new" anti-obesity agents!? I mean, it's quite obvious that the Koreans knew all along what keeps you lean ;-)

• Lactobacillus plantarum KY1032 cell extract - Before you begin to jubilee about the triumph march of probiotics, let me tell you this: I am not sure how on earth the remnants of a gut bacterium are supposed to reach your adipocyte tissue in a healthy individual without a leaky gut. Against that background I am not sure, whether it is even necessary to mention that Park et al. observed in 2011 that a cell exctract of the KY1032 strain of lactobacilli is another compound that can down-regulate the expression of peroxisome proliferator-activated receptor-γ2, CCAAT/enhancer binding protein-α, fatty acid synthase, and adipocyte-fatty acid binding protein and thus blunt fat gains in vitro... ah, now I wrote it down, so I'll just leave it here ;-) 

• Irvingia gabonensis seed extract - Likewise not a newcomer to the supplement the African / Southeast Asian tree, respectively an extract from its seeds has been shown to dose-dependently decrease the expression of PPAR-gamma in murine adipose cells in the petri dish in a 2008 study by scientists from  Faculty of Science, University of Yaoundé in Cameroon and the Wake Forest University School of Medicine in Winston-Salem, USA (Oben. 2008).

The in-vitro study shows, CAF may inhibit fat storage, but it does not "squeeze" the fat out of the cells (data based on Kim. 2012)

• Citrus aurantium falvenoids (CAF)- Despite the fact that most of you will probably have realized in N=1 experiments that citrus aurantium is a supplemental non-starter as a fatburner. It has (in-vitro) the ability to reduce the epxression of C/EBPβ and subsequently inhibit the activation of PPARγ and C/EBPα. So unless you have taken tons of pure CAF supplements during your last bulk, it is no wonder that you did not realize any effect from the fat burner you bought last summer. After all you are not storing any fat when you are dieting anyway... and I guess you have been dieting, when you took that product, right?
  
  Apropos dieting, the data in the figure on the right also shows that citrus aurantium, alone, won't help with that. After all it lacks the ability to increase LPL and thus the release of free fatty acids from the triglyceride stores in your fat stores.

• Silibinin (from milk thistle) - You will probably have heard that milk thistle can help replenish the antioxidative defenses of your liver and thus prevent all sorts of systemic toxicities (learn more). At least in-vitro silibinin (aka silybin), the major active ingredient in silymarin, can also prevent the accumulation of triglycerides in existing, as well as the formation / maturation of future adipocytes. From a mechanistic point of view, the effect is mediated by the usual suspects respectively their downregulation (CAAT/enhancer binding protein-alpha, fatty acid synthase, sterol response element binding protein 1c, adipocyte-specific lipid binding protein, peroxisome proliferator-activated receptor gamma and lipoprotein lipase; cf. Ka. 2009).

• Stem bromelain (SBM) - Just as so many of the previously mentioned agents, SBM, a specific member of the bromelain family you may know as "pineapple enzyme", is by no means a "new kid on the anti-fatloss block". Rather than that it has been used for centuries in traditional medicine as - guess what? - an anti-obesity agent. Now, I would never suggest that all TCM medicines work, but for stem bromelain it does at least seem as if the in-vitro studies, Dave et al. conducted about a year ago would support the notion that the ingestion of respective supplements can in fact exert beneficial effects on the accumulation of body fat (Dave. 2012).

  

  Illustration of the mechanism and selected downstream effects of stem bromelain (SBM) on fat cells in the petri dish (compiled based on data from Dave. 2012)

  At the molecular level, SBM targets the same adipogenesic genes as (almost all) of the previous agents. What's interesting though, is the fact that the scsientists also found that "SBM's ability to repress PPARγ expression seems to stem from its ability to inhibit Akt and augment the TNFα pathway." (Dave. 2012) In other words, it's the increase in "bad" TNF-alpha and the decrease in the purportedly muscle, but in fact simply "mass building" Akt-TSC2-mTORC1 pathway that entails the apoptosis (controlled cell death) of mature adipocytes and lipolysis.

With the stem bromelain this comprehensive, but by no means all-encompassing list of "proven" (mostly only in vitro) anti-adipogenic agents, has come full circle. After all, Dave et al. point out that their data would indicate that stem bromelain, together with all-trans retinoic-acid (atRA), which is a metabolite of vitamin A, the first item on our list "may be a potent modulator of obesity by repressing the PPARγ-regulated adipogenesis pathway at all stages and by augmenting TNFα-induced lipolysis and apoptosis in mature adipocytes." (Dave. 2010).

It's not just beyond the scope of this article, but - in the majority of the cases simply not known - whether or not the TNFα increase is an integral part of the anti-obesity effects of all of the aforementioned compounds. As far as the inhibition of PPAR-gamma is concerned things are different, though. With PPAR-gamma being the central "fat storage" switch, its deactivation and the entailing blockade of adipocyte differentiation, pre-adipocyte maturation and triglyceride storage is currently probably the most effective anti-obesity  mechanism we know. A mechanism that is way more fundamental than the diet-induced and stimulant / alpha/beta-agaonist (caffeine, ephedra, clenbuterol, yohimine) supported emptying of existing adipocyte triglyceride stores.

---

I know it's not popular, but in the case of vitamin D we already have evidence of it's obesity promoting effects (read more). It's straight forward experimental evidence, much contrary to the epidemiological guesswork on the basis of which people are popping vitamin D pills, these days.

Keep in mind: Most of the data is derived from in-vitro studies. Few compounds do have actual evidence from rodent studies and the number of substances that showed beneficial effects in human studies is even smaller.

Nevertheless, the above list harbors a number of compounds which could be of great interest for the lean physical culturist, for whom (at least physique-wise) stuff like vitamin D (note: the effects could be dose-dependent with benefits at low, and detrimental effects at high levels), astragalus and the rest of the healthy, but pro-adipogenic agents that can help obese individuals to stash away the tons of sugar and fat floating through their arteries are of little use.

Against that background I want to close this post with a warning, or I should say a reminder of the the fact that the effects of PPAR-gamma are physiologically important (e.g. prevention of lipotoxicity, Medina-Gomez. 2007) and go beyond "just making you fat" in how it would be worth striving to suppress it altogether is thus questionable (suggested read: CLA Destroys Body Fat). Since for all of the previously discussed agents that have in-vivo data to support their efficacy have postivite, not negative "side effects" (think of curcumin, gingerol, ginseng, etc.), it is yet unlikely that the use of reasonable amounts of one or a stack of many of them is going to harm you.

Just keep in mind: The goal should be to keep the PPAR-gamma activity in check, not to annihilate it. Consequently you should not and cannot expect to be able to "eat whatever you want and still stay lean" by supplementing with any of the agents above. On the other hand, they can hardly be even less useful than the vast majority of currently available arsenal of OTC "fat burners" ;-)

References:

• Berry DC, Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol Cell Biol. 2009 Jun;29(12):3286-96.
• Berry DC, DeSantis D, Soltanian H, Croniger CM, Noy N. Retinoic acid upregulates preadipocyte genes to block adipogenesis and suppress diet-induced obesity. Diabetes. 2012 May;61(5):1112-21. 
• Brown PN, Roman MC. Determination of hydrastine and berberine in goldenseal raw materials, extracts, and dietary supplements by high-performance liquid chromatography with UV: collaborative study. J AOAC Int. 2008 Jul-Aug;91(4):694-701.
• Brun PJ, Yang KJ, Lee SA, Yuen JJ, Blaner WS. Retinoids: Potent regulators of metabolism. Biofactors. 2012 Dec 22. doi: 10.1002/biof.1056. 
• Chen S, Li Z, Li W, Shan Z, Zhu W. Resveratrol inhibits cell differentiation in 3T3-L1 adipocytes via activation of AMPK. Can J Physiol Pharmacol. 2011 Nov;89(11):793-9.
• Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP. Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim Biophys Acta. 2012 Feb;1822(2):185-95.
• Hisada K, Hata K, Ichida F, Matsubara T, Orimo H, Nakano T, Yatani H, Nishimura R, Yoneda T. Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes. J Bone Miner Metab. 2013 Jan;31(1):53-63.
• Hong JH, Hwang EY, Kim HJ, Jeong YJ, Lee IS. Artemisia capillaris inhibits lipid accumulation in 3T3-L1 adipocytes and obesity in C57BL/6J mice fed a high fat diet. J Med Food. 2009 Aug;12(4):736-45.
• Hu Y, Davies GE. Berberine increases expression of GATA-2 and GATA-3 during inhibition of adipocyte differentiation. Phytomedicine. 2009 Sep;16(9):864-73. doi: 10.1016/j.phymed.2009.03.002. Epub 2009 Apr 28.
• Huang C, Zhang Y, Gong Z, Sheng X, Li Z, Zhang W, Qin Y. Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway. Biochem Biophys Res Commun. 2006;348:571–578.
• Hwang JT, Lee MS, Kim HJ, Sung MJ, Kim HY, Kim MS, Kwon DY. Antiobesity effect of ginsenoside Rg3 involves the AMPK and PPAR-gamma signal pathways. Phytother Res. 2009 Feb;23(2):262-6.
• Joo JI, Kim DH, Choi JW, Yun JW. Proteomic analysis for antiobesity potential of capsaicin on white adipose tissue in rats fed with a high fat diet. J Proteome Res. 2010 Jun 4;9(6):2977-87.
• Juman S, Yasui N, Okuda H, Ueda A, Negishi H, Miki T, Ikeda K. Caffeic acid phenethyl ester inhibits differentiation to adipocytes in 3T3-L1 mouse fibroblasts. Biol Pharm Bull. 2010;33(9):1484-8.
• Ka SO, Kim KA, Kwon KB, Park JW, Park BH. Silibinin attenuates adipogenesis in 3T3-L1 preadipocytes through a potential upregulation of the insig pathway. Int J Mol Med. 2009 May;23(5):633-7.
• Kim SK, Kong CS. Anti-adipogenic effect of dioxinodehydroeckol via AMPK activation in 3T3-L1 adipocytes. Chem Biol Interact. 2010a Jun 7;186(1):24-9.
• Kim KJ, Lee OH, Lee BY. Fucoidan, a sulfated polysaccharide, inhibits adipogenesis through the mitogen-activated protein kinase pathway in 3T3-L1 preadipocytes. Life Sci. 2010b May 22;86(21-22):791-7.
• Kim GS, Park HJ, Woo JH, Kim MK, Koh PO, Min W, Ko YG, Kim CH, Won CK, Cho JH. Citrus aurantium flavonoids inhibit adipogenesis through the Akt signaling pathway in 3T3-L1 cells. BMC Complement Altern Med. 2012 Apr 3;12:31.
• Kong CS, Kim JA, Eom TK, Kim SK. Phosphorylated glucosamine inhibits adipogenesis in 3T3-L1 adipocytes. J Nutr Biochem. 2010 May;21(5):438-43. 
• Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006;55:2256–2264. 
• Lee YK, Lee WS, Hwang JT, Kwon DY, Surh YJ, Park OJ. Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect through AMPKalpha-COX-2 in cancer cells. J Agric Food Chem. 2009 Jan 14;57(1):305-10.
• Lee H, Kang R, Yoon Y. SH21B, an anti-obesity herbal composition, inhibits fat accumulation in 3T3-L1 adipocytes and high fat diet-induced obese mice through the modulation of the adipogenesis pathway. J Ethnopharmacol. 2010 Feb 17;127(3):709-17.
• Liu Y, Wang WJ, Chen WH, Yin J. [Effects of Astragalus polysaccharides on proliferation and differentiation of 3T3-L1 preadipocytes]. Zhong Xi Yi Jie He Xue Bao. 2007 Jul;5(4):421-6.
• Liu Y, Lou SY, He YM. [Effects of berberine on cell proliferation, peroxisome proliferation activated receptor gamma, CAAT/enhancer binding protein mRNA and protein expression in 3T3-L1 pre-adipocytes]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2008 Nov;28(11):1005-9.
• Medina-Gomez G, Gray SL, Yetukuri L, Shimomura K, Virtue S, Campbell M, Curtis RK, Jimenez-Linan M, Blount M, Yeo GS, Lopez M, Seppänen-Laakso T, Ashcroft FM, Oresic M, Vidal-Puig A. PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. PLoS Genet. 2007 Apr 27;3(4):e64.
• Mukherjee R, Yun JW. Bromocriptine inhibits adipogenesis and lipogenesis by agonistic action on α2-adrenergic receptor in 3T3-L1 adipocyte cells. Mol Biol Rep. 2013 May;40(5):3783-92.
• Nimitphong H, Holick MF, Fried SK, Lee MJ. 25-hydroxyvitamin D₃ and 1,25-dihydroxyvitamin D₃ promote the differentiation of human subcutaneous preadipocytes. PLoS One. 2012;7(12):e52171.
• Oben JE, Ngondi JL, Blum K. Inhibition of Irvingia gabonensis seed extract (OB131) on adipogenesis as mediated via down regulation of the PPARgamma and leptin genes and up-regulation of the adiponectin gene. Lipids Health Dis. 2008 Nov 13;7:44.
• Park DY, Ahn YT, Huh CS, Jeon SM, Choi MS. The inhibitory effect of Lactobacillus plantarum KY1032 cell extract on the adipogenesis of 3T3-L1 Cells. J Med Food. 2011 Jun;14(6):670-5.
• Park UH, Jeong HS, Jo EY, Park T, Yoon SK, Kim EJ, Jeong JC, Um SJ. Piperine, a component of black pepper, inhibits adipogenesis by antagonizing PPARγ activity in 3T3-L1 cells. J Agric Food Chem. 2012 Apr 18;60(15):3853-60.
• Sagara C, Takahashi K, Kagechika H, Takahashi N. Molecular mechanism of 9-cis-retinoic acid inhibition of adipogenesis in 3T3-L1 cells. Biochem Biophys Res Commun. 2013 Mar 29;433(1):102-7. 
• Seo JB, Choe SS, Jeong HW, Park SW, Shin HJ, Choi SM, Park JY, Choi EW, Kim JB, Seen DS, Jeong JY, Lee TG. Anti-obesity effects of Lysimachia foenum-graecum characterized by decreased adipogenesis and regulated lipid metabolism. Exp Mol Med. 2011 Apr 30;43(4):205-15.
• Thounaojam MC, Jadeja RN, Ramani UV, Devkar RV, Ramachandran AV. Sida rhomboidea. Roxb Leaf Extract Down-Regulates Expression of PPARγ2 and Leptin Genes in High Fat Diet Fed C57BL/6J Mice and Retards in Vitro 3T3L1 Pre-Adipocyte Differentiation. Int J Mol Sci. 2011;12(7):4661-77.
• Tzeng TF, Chang CJ, Liu IM. 6-Gingerol Inhibits Rosiglitazone-Induced Adipogenesis in 3T3-L1 Adipocytes. Phytother Res. 2013 Mar 21.
• Wang JM, Yang Z, Xu MG, Chen L, Wang Y, Su C, Tao J. Berberine-induced decline in circulating CD31+/CD42- microparticles is associated with improvement of endothelial function in humans. Eur J Pharmacol. 2009;614:77–83.
• Yuan HD, Yuan HY, Chung SH, Jin GZ, Piao GC. An active part of Artemisia sacrorum Ledeb. attenuates hepatic lipid accumulation through activating AMP-activated protein kinase in human HepG2 cells. Biosci Biotechnol Biochem. 2010;74(2):322-8.
• Yuan HD, Piao GC. An active part of Artemisia sacrorum Ledeb. inhibits adipogenesis via the AMPK signaling pathway in 3T3-L1 adipocytes. Int J Mol Med. 2011 Apr;27(4):531-6.

Science Round-Up Seconds: Follow-Up on Gum Arabic for Fat Loss. DMAA or Schizandra, Which Caused a Stroke in a Young Soldier? Low Doses of Resveratrol Better Than High Ones? Vitamin E Keeps Diabetic Brains Intact.

When it's served like this, Gum Arabic looks more like a healthy snack than a weight loss adjuvant.

I guess everyone who has already listened to the podcast of yesterday's show or was even able to listen live, will have noticed that the audio quality - yet not my German accent - have improved significantly, now that Carl and I did eventually switch to Skype instead of the landline. I know, you have been telling me that all along... be that as it may, unless my Internet connection hangs up for whatever reasons we will continue to do the SuppVersity Science Round-Ups via Skype from now on. Apropos, there will definitely be another show next Thursday (assuming that the world did not collapse by then ;-)

Follow up on Gum Arabic: Dosing & mechanism

In addition to that, I was actually presently surprised how much ground we were able to cover. Allegedly, we have gone way over the scheduled 60min, and I guess I could have said a couple of additional words on the Gum Arabic study and the astonishing fat loss results what I did mention was that it works astonishingly well, what I did not tell you about - or I have forgotten I did (too little caffeine I guess ;-) - is the dosage and the mechanism of action. At least as far as the former is concerned there is no debating that the fat loss magic (-2.1% from ~20% body fat to ~18% in 6 weeks; cf. Babiker. 2012) happened with just 30g of the substance that's derived  from exudates of Acacia senegal or Acacia seyal trees per day. Oher than the diarrhea and bloating, I did already mention on the show, the on average 19-year old perfectly healthy young women in the active arm of the study complained about nausea (82% in the first week) and an  "unfavourable oral viscous sensation" (100% in the first week). The latter is particularly interesting, because it does actually give us a hint on the underyling mechanism which is "not yet fully elucidated, because of a small number of conducted studies" (on its weight loss effects, but could be related to the increase in plasma leptin (without resistance obviously) as well as the increased fatty acid oxidation in muscle tissue in response to viscous fiber ingestion Islam et al. have reported only recently in Obesity (Silver Spring) earlier this year (Islam. 2012). I guess that we are going to see follow up studies on this one pretty soon and you all know that the Science Round Up and of course the SuppVersity news is where you are going to read about them first ;-)

Now that we lost the working weight loss adjuvants behind us, let's get to one which doesn't have any record of helping with weight and was still in each and every fat burner on earth before it was banned: DMAA (1,3 dimethylamylamine) aka geranium oil or geranium extract.

DMAA induced stroke in young soldier!? Or is it maybe the Schizandra that's to blame?

We all know that the job of a soldier is dangerous. A recently published case-report in Military Medicine does yet show that these dangers may not always be due to standing in the line of fire, but can also arise as a consequence of having too much DMAA supplements in your stash (Young. 2012) :

Is schizandra to blame? While the data is in fact scarce and the overall understanding of it's effects would suggest that the TCM herb would rather protect than harm the brain, it is at least worth noting that (a) schizandra has been found enhance the stimulation of the dompaminergic system (Chang. 1991) and (b) that we know that the abuse of cocaine has very similar effects on neurotransmitters (Prakash. 1993) and is associated with an increased risk of hemorrhagic stroke (Kousik. 2012)

"A 26-year-old male was presented to a military treatment facility in Afghanistan shortly after taking a weight-lifting supplement called Jack3d with a severe headache and was subsequently found to have suffered a Dejerine-Roussy variant right thalamic hemorrhagic stroke. Jack3d active ingredients include geranamine, schizandrol A, caffeine, β-alanine, creatine monohydrate, and L-arginine α-ketoglutarate. A literature search revealed case reports suggesting some of the constituent ingredients may predispose to stroke and hemorrhage and also revealed a substantial paucity of data existed regarding schizandrol A, a herb used in traditional eastern medicine." (Young. 2012)

Now, you always have to take case reports like this with an appropriate amount of skepticism - specifically, when the subject has a personal interest of not disclosing all the "supplements" he may have been taking in order not to lose is job. That being said, you know my take on DMAA from the round-table discussion with Patrick Arnold, Kurtis Frank, and one of the guys from Ergo Log. Bottom line: There really isn't any reason to be pissed of by the ban. Even if it's not to prevent stroke, it will prevent the onset of chronic fatigue syndrome in many aspiring physical culturists.

A re-appreciation of vitamin E and resveratrol

"Regular" vitamin E, i.e. alpha tocopherol, has gotten somewhat of a bad rep as of late and whenever resvertatrol is found to produce any the myriad astonishing health effects scientists have identified, it's either these effects occur either in the petri dish or in a rodent model with (often injected) mega-doses you imply couldn't afford taking on a regular basis. In this regard, a recently published paper which reports profound reductions in the fatty acid synthase, and fatty acid oxidation in the livers and adipose tissue of mice in response to a 0.005% resveratrol enriched high fat chow (this would be ~36mg/day for a human) is yet more than only an exception to the rule (Cho. 2012).

Figure 1: Metabolic effects of high fat diet (HFD) or HFD with two different doses of resveratrol; data expressed relative to mice on a standard diet (Cho. 2012)

I mean, take a look at the effects this low dose had compared to the 4x higher dosing in a second group of mice who received the human equivalent of ~142mg/day (see figure 1). Is this really another instance where more does not only yield no additional benefits, but actually reduces the effect (incidentally, de la Lastra et al. have discussed the pro-antioxidant effects of high doses of resveratrol in 2007 already; cf. de la Lastra. 2007)? Or is this just because "mice are no little human beings" and the results are therefore meaningless for us?

If you believe the latter is the case, I suggest you simply scroll down to the overview of some recent facebook news instead of reading how the adminstration of vitamin E to alloxan-induced diabetic rodents (standard model for type II diabetes) did ameliorate the shrinkage of Purkinje cells and apoptosis of cells in the granular layer, the mitochondrial defects, the splitting  of the myelin sheaths and widening axonal spaces, as well as the decrease in the number of GFAP-positive astrocytes (those that still produce a protein, namely GFAP that's responsible to keep their structure intact) in the cerebellar cortex (Mohammed. 2012)

 + + + + + + + + + + + + + +

That's it for today: You know the holiday season is coming so having too many Seconds isn't a particular good idea these days. If you still need something I suggest you pick one of the easily digestible Facebook news, for example...

• GI, GL and cancer risk - While there are statistically significant associations, only the ones for the glycemic load, which adds another quality factor namely GI + carbs per 100g to the equation, appear to have real world significance, though (read more)
• Folic acid in pregnancy - It's not all gold that glitters in ads and carries the letters "RDA". Among the profound epigenetic effects that have been observed in rodent studies, some sound as if they were from a list of the most rampant current pathologies (read more)
• Adiposity will shrink your brain - Leptin resistance is associated with reduced brain volume, associations persist even when they are corrected for BMI (read more)

You know there is more and there is even more to come. So in case the world does not explode within the next hours you know where to go if you are bored waiting for the "Zombie Repopulation" to happen.
 
References:

• Babiker R, Merghani TH, Elmusharaf K, Badi RM, Lang F, Saeed AM. Effects of gum Arabic ingestion on body mass index and body fat percentage in healthy adult females: two-arm randomized, placebo controlled, double-blind trial. Nutr J. 2012 Dec 15;11(1):111. 
• Cho SJ, Jung UJ, Choi MS. Differential effects of low-dose resveratrol on adiposity and hepatic steatosis in diet-induced obese mice. Br J Nutr. 2012 Dec;108(12):2166-75.
• de la Lastra CA, Villegas I. Resveratrol as an anti-oxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans. 2007;35:1156–1160.
• Islam A, Civitarese AE, Hesslink RL, Gallaher DD:  Viscous dietary fiber reduces adiposity and plasma leptin and increases muscle expression  of fat oxidation genes in rats. Obesity (Silver Spring)2012, 20(2):349–355.
• Kousik SM, Napier TC, Carvey PM. The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation. Front Pharmacol. 2012;3:121.
• Prakash A, Das G. Cocaine and the nervous system. Int J Clin Pharmacol Ther Toxicol. 1993; 31:575–581.
• Young C, Oladipo O, Frasier S, Putko R, Chronister S, Marovich M. Hemorrhagic Stroke in Young Healthy Male Following Use of Sports Supplement Jack3d. Military Medicine. December 2012; 177(12): 1450-1454(5).
• Zhang L, Niu X. [Effects of schizandrol A on monoamine neurotransmitters in the central nervous system]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1991 Feb;13(1):13-6.

Leucine + Resveratrol - Synergistic Sirtuin Boosters: +118% Fatty Acid Oxidation, 60% Increase In Muscular Glucose Uptake, -30% Visceral Fat & More - To Good to be True?

Image 1: Can you really team up leucine (or HMB) and resveratrol to make tired mitochondria get a move on? NuSirt Sciences says "YES!" And in the dish and rodents it's actually already working.

What happens if you marry a well-known AMPK promoter and exercise mimetic, with an even more prominent exercise adjuvant and nutritional mTOR booster? Will they neutralize each other? Think about it.... ok, now gimme your answer: What happens if you put resveratrol and leucine together? At first it does not really make sense, does it? Right, it doesn't, at least not unless you follow the same train of thought, the researchers from NuSirt Sciences. NuSirt? That rings a bell, hah? Yeah those were the guys who did a study on their 250mg leucine + 30mg vitamin B6 proprietary blend NuFit (see "Testosterone - 12% Drop /W 75g Glucose? Fat Loss - Adzuki, Leucine + B6 or HiMaize & More") and actually, the leucine + resveratrol combination is sort of a spin-off of this initial research.

If you put Sirt1 & Sirt1 together, it suddenly makes sense!

In their latest study (and you bet a future product!) Bruckbauer et al. build on their previous research on the agonistic effects HMB, alpha-KIC or leucine have on skeletal muscle Sirt-1 activity (Bruckbauer. 2011) and rationalize that it seems legit to combine one Sirtuin portein promoter with another one in order to achieve an even more pronounced effect - makes sense, right? Resveratrol the proven AMPK-promoter and igniter of the longevity, gene transcription, cell survival and apoptosis regulating Sir2 proteins (=sirtuins) and leucine the mTOR promoting and, as of late, proven Sirt1 agonist, they could actually form a synergistic duo for fat oxidation, glucose management, the reduction of oxidative stress and inflammation and even longevity!

Figure 1: Effects on sirtuin & AMPK expression in muscle and fat cells upon incubation with leucine, HMB and resveratrol and the respective combinations (left) and effects fatty acid oxidation in isolated rat skeletal muscle upon incubation in low and high glucose conditions (data based on Bruckbauer. 2012)

Now, aside from Sirt1, which is mainly expressed in the nucleus of a cell, another one of the Sir2 proteins, Sirt3, which is expressed predominantly in the mitochondria has as of late gathered quite some attention, as mitochondrial dys- or malfunction is one, if not the common denominator of many of the pathological features of the metabolic and neuro-endocrine ailments the Western diabesity society is suffering from: insulin resistance, type II diabetes, Alzheimer's , you name them! No wonder the NuSirt guys (and girls) are striving to find a marketable way to set them both in full gear and if you take a closer look at the data in figure 1 their initially counter-intuitive approach to bath muscle and fat cells in resveratrol  + HMB / leucine solutions yields impressive results:

• resveratrol, leucine and HMB, alone, exerted only weak independent effects on Sirt1, Sirt 3 and AMPK
• resveratrol and leucine or HMB, combined, yielded Sirt1 and Sirt3 activity increases in the ~50% range (p < 0.05) and AMPK increases of +42% and +55% (p < 0.03); particularly noteworthy are the ~125-175% increases (p < 0.02) muscle cells (remember: Sirt3 is expressed in the mitochondria!)
• the ensuing increases in fatty acid oxidation in incubated muscle cells reached statistical significance in the presence of low (5 mM) glucose levels, only, when and 5 µM HMB or  0.5 mM leucine were co-incubated with 200 nM (~18%; p < 0.05), in the high glucose condition, however, all treatments broad about significant increases in fatty acid oxidation, of which those in the leucine- and HMB-resveratrol combination treatments were the most pronounced (118% and 91% stimulation, respectively; p < 0.005)

Especially the last finding, i.e. the increase in fatty acid oxidation in an in-vitro condition that resembles the hyperglycemic state the average type II diabetic who is not popping tons of metformin and/or injecting insulin is constantly in, makes these results particularly interesting, as it appears as if a "non-pharmacological" (what by the way is "pharmacological" and what isn't?) solution to the diabesity problem could already be hidden on the shelves of your GNC right next door (I assume they carry leucine and resveratrol products ;-)!

Outside of the box... ahh, I mean, ... the petri dish!

In view of the fact that 75% of the in-vitro high performers suck in the rodent model already and of those another 75% don't work in human trials you will be pleased to hear that NuScirt Sciences' resveratrol + leucine / HMB combination has already overcome the first of these hurdles: At least in DIO (diet-induced-obese) rodents who on a 6-week high fat diet regimen, the combination works.

Figure 2: Weight gain, visceral adipose volume, PET measured palmitate uptake, respiratory rate (lower levels = higher relative fat oxidation), heat production relative to body weight, food intake; all value expressed relative to DIO mice who were maintained on an unsupplemented control diet (data based on Bruckbauer. 2012)

Now, it's not as if the rodents would have made it to the Mr Olympia stage, but if you take a closer look at the pattern that's emerging here, it's quite clear that the sirtuin booster does its job in this rodent model. Aside from its ameliorative effect on weight gain, the combination of resveratrol and leucine, led to statistically significant improvements in glucose management and improvements in inflammatory markers (including the anti-inflammatory adipokine adiponectin, see figure 2).

Figure 2: Glucose, insulin and HOMA IR levels, muscular glucose uptake (left), C-reactive protein , IL-6, MCP-1 and adiponectin (right) ; all value expressed relative to DIO mice who were maintained on an unsupplemented control diet (data based on Bruckbauer. 2012)

Most importantly, however it effectively cut through the exuberant amount of visceral adipose tissue (>30% reduction), ramped up the palmitate (fatty acid) uptake, oxidation and heat production (=thermogenesis). Despite all these metabolic improvements which took place in the absence of a simple reduction in food intake, there are still a couple of things left to be desired:

What are the human equivalent doses, here? Since I know you would be asking I did the math for you and you will be pleasantly surprised (HED for 80kg humans)

• 12.5mg resv. = 9mg
• 225mg resv. = 136mg
• 2g HMB = 1.1-1.4g
• 10g HMB = 7.2g
• 24g leucine = 14.3g

I am well aware that it must look as if I had the typical poor arithmetic abilities of the average physicist who has totally forgotten how to calculate using figures instead of letters, but the reason for the discrepancies is that I calculated the exact HEDs based on body weight and food intake for each of the groups.

1. Supplementation with the respective human equivalent doses should yield the same astonishing results in humans as it did in the diet-induced obese mice.
2. The protocol should have effects not just in morbidly obese diabetic human beings, but also in overweight and ideally even lean individuals.
3. The supp must work if you don't put it into the chow, but pop it in separate doses (e.g. 3x/day) as a capsule or tablet.

The good news however is that if 1-3 apply, you could start benefiting from this "super supplement" right now! After all, the resveratrol dose of 12.5mg per kilogram of chow (the mice in the study did not consume more than max. 4g(!) per day) is so low that the 10g package I just saw for 20$ over at the webshop of a major bulk supplier would last you literally forever ...

Unfortunately, this is exactly why I don't believe that LeuResSirt, or whatever other stupid name the final product will be given, is going to work - I mean, come on, you can't tell me that there are not already people out there who get 15-20g of leucine everyday and pop resveratrol in 100x the necessary dose of 8-9mg everyday!? And did they turn into a beast, become fast-food resistant or lose fat magically? What? Yeah... that must be Phil Heath secret, right... how come I did not realize that before? ;-)

Bottom line: Regardless of the probably justified skepticism, I will still keep you posted on whether or not NuSirt knocks out another incredible (in the literal sense) human study like the one on NuFit (see "Testosterone - 12% Drop /W 75g Glucose? Fat Loss - Adzuki, Leucine + B6 or HiMaize & More"). So stay tuned, you all know that no supplement will ever more ergogenic than your daily dose of SuppVersity news!

References:

• Bruckbauer A, Zemel MB. Effects of dairy consumption on SIRT1 and mitochondrial biogenesis in adipocytes and muscle cells. Nutr Metab (Lond). 2011 Dec 20;8:91.
• Bruckbauer A, Zemel MB, Thorpe T, Akula MR, Stuckey AC, Osborne D, Martin EB, Kennel S, Wall JS. Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice. Nutr Metab (Lond). 2012 Aug 22;9(1):77.

Build a Bigger Mitochondrial Engine and Double Your Endurance With Chitooligosaccharides! Glucosamine Mix from Chitosan Acts on Sirt1 & AMPK, Similar to Resveratrol

Figure 1: Glucosamine composition of the chitooligosaccharide used in the study (data adapted from Jeong. 2012).

Usually I try to avoid this term, as it seems to imply that there is, or at least soon will be a pill that would allow you to stay the lazy bastard you are now and still make it into your old age, healthy lean, attractive and vigorous, but in this case the word "exercise mimetic" is unquestionably what describes the effects of 6 weeks of oral supplementation with chitooligosaccharide described in a recently published paper by scientists from the Amorepacific Corporation Research & Development Center and the Kyung Hee University in South Korea best. I have to give props to my friend Carl Lanore the voice (and brain) of Super Human Radio who shot me an email on this issue, yesterday.

A brief glance at the full-text was enough to realize that Carl who likes to pretend he was the idiomatic "blind man" with no scientific degree (I could hardly care less, by the way ;-) who hits upon things like this only perchance was up to something - those who now the show, will be aware that he is smarter than many of the experts he interviews, anyways... but I am getting derailed, here. Where was I? Ah yeah, the study...

COS - What we already know

• Ameliorates weight gain (-15%) and high blood lipids on HFD in mice in the absence of reduced energy intake (Choi. 2012)
• Promotes cytokine release in intestinal epithelial cells (Bahar. 2012)
• Inhibits pancreatic lipase and thus breakdown and subsequent uptake of dietary fat (Kang. 2012)
• Suppresses TNF-alpha induced collagen breakdown in-vitro (Ryu. 2012)
• Has neuroprotective effects (Joodi. 2011)

Promising in vivo rodent + in vitro cell line data: Very promising, but not yet field-tested

Hyun Woo Jeong and his colleagues fed 39 female Sprague-Dawley rats either normal or 0.05% chitooligosaccharide (COS produced by Bioland Korea Co. Briefly from chitosan by enzyme digestion, followed by deacetylation of chitin; cf. Hirano. 1989) enriched rodent chow for 6 weeks.

At the end of the study period, 50% of the rodents had performed an exercise test on the treadmill, in the course of which they had to run at a pace of 20m/min until exhaustion, while the rest of the animals were sacrificed before this final workout to assess their pre-exercise plasma profiles including ALT, AST, triglyceride, total cholesterol, lactate, and free fatty acid levels (none of which showed significant changes over the course of the 6-week study period).

Despite the fact that the scientists did not measure the total lean and fat mass of the rodents, the collective data in figure 2 clearly suggests that the -72% reduction in weight gain was not at the expense metabollically active muscle tissue.

Figure 2: Body weight and energy intake (left) and muscle weight vs. body weight (right) data at the end of the 6-week trial (data adapted from Jeong. 2012).

Despite a statistically non-signficant reduction in food intake (-6%) the chitooligosaccharide treated rodents had heavier soleus (slow twitch, type II fiber dominant muscle) muscles and a more favoreable plantaris (fast twitch, type II-X fiber dominant muscle) to total body weight ratio (indicative of a lower body fat percentage), than their non-supplemented peers. Moreover, a cursory glance at figure 3 does also reveal why this is the case.

Figure 3: Electron microscopic image of muscle tissue (top; small arrows and green areas indicate the presence of mytochondria), mitochondrial density in in-vitro control experiment after exposre to different doses of  resveratrol vs. chitooligosaccharide (bottom, left) and time to exhaustion during treadmill test (adapted from Jeong. 2012)

Even as a non-expert it is easy to see that the chitooligosaccharides had profound "anabolic" effects on the mitochondria of the lab animals.

COS activated AMPK and increased the cellular NAD+ / NADH ratio to induce Sirt1 activation. The activation of AMPK and Sirt1 increased the expression and activity of PGC1 and augmented the expression of mitochondrial genes. As a result of activation of AMPK, Sirt1, and PGC1, COS facilitated mitochondrial biogenesis. In rodents, the administration of COS significantly increased intramuscular mitochondrial content, resulting in enhanced exercise endurance and reduced plasma lipid profiles. (Jeong. 2012)

In the Petri-dish, it may be less potent than resveratrol on a per mg base (figure 3, bottom-left), but the real world effects in terms of both, increased mitochondrial biogenesis (see green mitochondria in the electron microscopic image of skeletal muscle; figure 3, top) and subsequent increases in average running time to exhaustion (+96%; figure 3, bottom right) speak for themselves.

Implications: Other than resveratrol, which has an oral biovailability that is hardly high enough to be quantified (Walle. 2004), chitooligosaccharide could actually be suitable for oral supplementation - at least if we assume similar pharmacokinetics in humans as in rats (which is likely, but not necessarily the case).

• especially sedentary individuals or people who rarely train could benefit from the exercise-mimicking effects 
• in a previous study by Cho et al. chitooligosaccharide lactate has been found to be superior to chitooligosaccharide HCL (Cho. 2010)
• the optimal dosage and, more importantly, whether trained and well-conditioned individuals would benefit to a similar extend / at all, would yet require further studies. 
• the human equivalent dosages for the study at hand would be 600-900mg/day depending on the individuals body weight

Image 1: COS is rather something for the "old" Mr C. than for Adelfo

Aside from the fact that there are (at least to my knowledge) no over-the-counter chitooligosaccharide supplements on the market, so that you would probably have to order a metric ton right from China at Alibaba.com, I would not expect too much from it, anyways. Firstly, the chances that it turns out to be another supplemental non-starter like resveratrol are high. And second- and more importantly, the beneficial effects will be less pronounced for well-conditioned individuals and could even be close to zero (and certainly not practically relevant) for people who go to the gym to train and not to pose, to chat or to flirt. People like you and me and Adelfo Cerame, whose new client Mr. C. is soon going to join the ever-growing community of physical culturists, who don't need a "mimetic" for something they love: Exercise!

References:

• Bahar B, O'Doherty JV, Maher S, McMorrow J, Sweeney T. Chitooligosaccharide elicits acute inflammatory cytokine response through AP-1 pathway in human intestinal epithelial-like (Caco-2) cells. Mol Immunol. 2012 Jul;51(3-4):283-91. Epub 2012 Apr 16.
• Cho SY, Lee JH, Song MJ, Park PJ, Shin ES, Sohn JH, Seo DB, Lim KM, Kim WG, Lee SJ. Effects of chitooligosaccharide lactate salt on sleep deprivation-induced fatigue in mice. Biol Pharm Bull. 2010;33(7):1128-32.
• Choi EH, Yang HP, Chun HS. Chitooligosaccharide ameliorates diet-induced obesity in mice and affects adipose gene expression involved in adipogenesis and inflammation. Nutr Res. 2012 Mar;32(3):218-28.
• Hirano S, Tsuchida H, Nagao N. N-acetylation in chitosan and the rate of its enzymic hydrolysis. Biomaterials. 1989;10: 574–576.
• Jeong HW, Cho SY, Kim S, Shin ES, Kim JM, Song MJ, Park PJ, Sohn JH, Park H, Seo DB, Kim WG, Lee SJ. Chitooligosaccharide Induces Mitochondrial Biogenesis and Increases Exercise Endurance through the Activation of Sirt1 and AMPK in Rats. PLoS One. 2012;7(7):e40073.
• Joodi G, Ansari N, Khodagholi F. Chitooligosaccharide-mediated neuroprotection is associated with modulation of Hsps expression and reduction of MAPK phosphorylation. Int J Biol Macromol. 2011 Jun 1;48(5):726-35.
• Kang NH, Lee WK, Yi BR, Park MA, Lee HR, Park SK, Hwang KA, Park HK, Choi KC. Modulation of lipid metabolism by mixtures of protamine and chitooligosaccharide through pancreatic lipase inhibitory activity in a rat model. Lab Anim Res. 2012 Mar;28(1):31-8. Epub 2012 Mar 21.
• Ryu B, Himaya SW, Napitupulu RJ, Eom TK, Kim SK. Sulfated chitooligosaccharide II (SCOS II) suppress collagen degradation in TNF-induced chondrosarcoma cells via NF-κB pathway. Carbohydr Res. 2012 Mar 1;350:55-61.
• Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004 Dec;32(12):1377-82. Epub 2004 Aug 27.

Resveratrol from 100l of 1994 Pinot Noir Could Increase Fat Oxidation by 71%, Strength by 18-58% and Endurance by 20% - At Least, If You Could Afford and Drink It Every Day!

Image 1: Itadori (Japanese Knotweed) and selected varieties of red wine are the best yet vastly 'underdosed' sources of resveratrol (see red box, below)

At least in rodents, resveratrol, the red-wine polyphenol, has been shown to act as an exercise mimetic, exerting profound effects on PGC-alpha expression which protect muscle from wasting due to mechanical unloading (also know as extreme couch-potato-ing ;-) and rodents from the negative side-effects of obesogenic diets by directly modulation gene expression, lipid transport and fatty acid oxidation in skeletal muscle (Chen. 2011; Momken. 2011). Still, most of the oftentimes publicly puffed up data on resveratrol comes from in-vitro studies with dosages of which even the researchers often believe that they are not attainable via oral supplementation.

Rodents or petri dishes? Humans would be too expensive...

Compared with the aformentioned in vitro data, the numbers and gene essays in a recently published study by scientists from the University of Alberta are actually of great practical relevance (Dolinsky. 2012), because Dolinsky et al. administered their resveratrol orally* (4g in 1kg chow) to healthy rats and - what's even more important for the average trainee - 50% of those rats were exercised for 60min, 5x per week on a treadmill (10m/min to 20m/min; cf. Fenning. 2003) for 12 weeks.

Figure 1: Resveratrol content of selected red-wines and Itadori (Japanese knotweed) tea (based on Burns. 2005; equivalent consumption based on dose used in Dolinsky. 2012)

*Can I get my resveratrol from wine or food: I cannot emphasize enough that with ~75% of orally administered resveratrol being excreted via feces and urine and an oral bioavailability of resveratrol of almost ZERO (Vitaglione. 2005; Wenzel. 2005), there is no reason whatsoever to cope with any of the ~100 in-vitro studies that are published on a monthly basis hailing resveratrol for this and that and praising it as the god-sent natural remedy for every ailment, except the consistent ignorance towards the profound difference between a cell in a petri dish and a complex organism that is so prevalent among the human lab rats in their white coats, these days. And the data in figure 1 should make it pretty clear that similar benefits as they were observed in the study at hand are not just unlikely, they are simply impossible to be achieved without highly concentrated supplements - or do you want to drink 105+ liters of wine a day to get your daily dose of ~2g of resveratrol?

Let's assume you got the ~350$ for your 2g/day of resveratrol powder** to mix with your food (**calculated based on the current price of >90% pure bulk powder in Europe), what would be the results? Would you lose weight? Unlikely. Would you lose body fat? Possible! Would you gain muscle? Very unlikely. So what's all the fuss about then?

Figure 2: Body weight (in g), time to exhaustion (in min) and distance covered (in m) during a treadmill exercise test at the end of the 12-week study period (based on Dolinsky. 2012)

Much ado about nothing? Not really, no. After all, the ~20% increase in endurance (time to exhaustion and distance covered; cf. figure 2)  did not come out of nowhere and do - and this is actually the main reason this study did actually make it to SuppVersity - add to the benefits of regular training. The "resveratrol rats" had ...

Image 2 (ADAM): Resveratrol has already been shown to prevent pathological hypertrophy of the heart muscle by AMPK / AKT modulation (Chan. 2008)

• greater strength gains +18% tibialis anterior twitch force and +58% and +22% tetanic and twitch force, respectively, in soleus vs. training alone
• improved cardiac function as assessed by statistical significant improvements in left ventricular ejection fraction and decreased isovolumic relaxation time, as well as increased ratio of the peak mitral flow velocity (E-wave) to the peak velocity of the late filling wave of atrial contraction
• decreased cardiac stress due to a -30% reduction in left ventricular wall stress vs. training alone
• higher VO2 ~10% during the active period 
• increased PPAR signalling and fatty acid metabolism in the heart (+8.8% and +10.3% respectively; p < 0.00001)

Sexier than the strength gains and the utterly unsexy (but vitally important) improvements in cardiac performance are yet the statistically significant reduction in triglycerides which should help insulin sensitivity (not measured in the study) and are probably a beneficial downstream effect of the  resveratrol induced shift towards higher fatty acid and lower glucose oxidation (-6% respiratory exchange ratio, RER; cf. figure 3) that went hand in hand with a highly significant +71% increase in fatty acid oxidation:

Figure 1: Triglyceride levels, free fatty acids, respiratory exchange ratio (higher values = lower fat oxidation, higher glucose oxidation) and total fat oxidation at the end of the 12-week study period (all data expressed relative exercised control; based on Dolinsky. 2012)

Along with the +50% increase in AMPK (vs. exercise alone) and the 20% increase in the "mitochondrial builder" PGC1-alpha (cf. "Two days on High Fat Diet Increase the Activity of Irisin Releasing Transcription Factor PGC1-α") it is obvious that, taken at the right dosage, resveratrol is not the supplemental non-starter everyone is let to believe who spent $30 for 60 100mg caps of resveratrol and took a 3-day dose (3x 2g!) spread across a whole month - obviously without the desired outcomes result.

At the moment resveratrol is still an expensive toy for scientists

Table 1: Significant changes in heart muscle gene expression (based on Dolinsky. 2012)

As a tool to study (epi-)genetics and the downstream effects and interactions of reduction of cytokines, such as the inteferon-induced proteins, which regulate immune functions, cell growth and apoptosis (Sen. 2000), increases in mitochondrial uncoupling protein 3 (UCP3) and UCP1, higher expressions of adiponectin and thyroid responsive protein and the steroyl-coenzyme A desaturase-1 enzyme, which converts saturated to mono unsaturated fatty acids and plays an important role in controlling inflammation, preventing atherosclerosis, steatohepatitis (fatty liver) and pancreatic beta cell dysfunction (Brown. 2010) resveratrol is a must have. As one of the most expensive currently available supplement with little to no actual human data from studies on healthy subjects, its usefulness for physical culturists is questionable and its cost-benefit ratio is abysmal, to say the least.

References:

1. Brown JM, Rudel LL. Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery. Curr Opin Lipidol. 2010 Jun;21(3):192-7. 
2. Burns J, Yokota T, Ashihara H, Lean ME, Crozier A. Plant foods and herbal sources of resveratrol. J Agric Food Chem. 2002 May 22;50(11):3337-40. 
3. Chan AY, Dolinsky VW, Soltys CL, Viollet B, Baksh S, Light PE, Dyck JR. Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt. J Biol Chem. 2008 Aug 29;283(35):24194-201. Epub 2008 Jun 18.
4. Chen LL, Zhang HH, Zheng J, Hu X, Kong W, Hu D, Wang SX, Zhang P. Resveratrol  attenuates high-fat diet-induced insulin resistance by influencing skeletal muscle lipid transport and subsarcolemmal mitochondrial β-oxidation. Metabolism.  2011 Nov;60(11):1598-609. 
5. Dolinsky VW, Jones KE, Sidhu RS, Haykowsky M, Czubryt MP, Gordon T, Dyck JR. Improvements in Skeletal Muscle Strength and Cardiac Function Induced by Resveratrol Contribute to Enhanced Exercise Performance in Rats. J Physiol. 2012 Apr 2. [Epub ahead of print]  Epub 2011 May 31.
6. Fenning A, Harrison G, Dwyer D, Rose'Meyer R, Brown L. Cardiac adaptation to endurance exercise in rats. Mol Cell Biochem. 2003 Sep;251(1-2):51-9.
7. Momken I, Stevens L, Bergouignan A, Desplanches D, Rudwill F, Chery I, Zahariev A, Zahn S, Stein TP, Sebedio JL, Pujos-Guillot E, Falempin M, Simon C, Coxam V, Andrianjafiniony T, Gauquelin-Koch G, Picquet F, Blanc S. Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB J. 2011 Oct;25(10):3646-60.
8. Sen GC. Novel functions of interferon-induced proteins. Semin Cancer Biol. 2000 Apr;10(2):93-101.
9. Vitaglione P, Sforza S, Galaverna G, Ghidini C, Caporaso N, Vescovi PP, Fogliano V, Marchelli R. Bioavailability of trans-resveratrol from red wine in humans. Mol Nutr Food Res. 2005 May;49(5):495-504.
10. Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005 May;49(5):472-81.