Seabuckthorn Leaves Increase PPAR-Alpha & PPAR-Gamma Expression, Keep the Liver Fat Free and Fatty Oxidation Up. Plus: PPARs - High or Low? How Are They Supposed to Be?

This time, the magic is in the leaves, not the fruits or kernels. And it's dose dependent. With an almost linear increase from 500-1,000mg/kg

Honestly, I don't think that it is coincidence that many of the most promising medical plants are shrubs that live on barren soil, like sand dunes and cliffs and are full of thorns as well as innate polyphenolic defense mechanisms. Whatever the "evolutionary" basis may be, if we go by the beneficial metabolic effects, researchers from the Department of Food Science and Human Nutrition at the Chonbuk National University in the Republic of Korea, it appears worth going through all the traditional used folk medicine across the world and identify which of them work, how they work and whether they may already have what it takes to get rid of one or the other of the typical Western diseases.

In the case of the ethanolic extract of seabuckthorn (Hippophae rhamnoides L) Pichiah et al. used in their most recent experiment, this would be ameliorative effects on weight gain through down-regulation of adipogenic and lipogenic gene expression.

Less weight gain more fatty acid turnover, better glucose management and leptin sensitivity

The ameliorative effects on the detoriation of glucose metabolism, the reduced but still significant weight gain of the 60% fat diet (additional fat 100% from lard) and the profound overexpression of leptin, which is indicative of the fact that the mice developed full-blown leptin resistance within the 13-weeks of HFD administration, were all ameliorated to a greater degree in the high dose seabuckthorn leaf extract group (human equivalent  ~6.5g/day).

Figure 1: Effect of the different diets on weight gain, visceral fat weight, feed intake and energy intake (left; data expressed relative to control diet); effects on blood sugar (AUC in glucose tolerance test) and leptin (Pichiah. 2012)

The differences between high and low dose supplementation of the extract which had been prepared by

"[...] by soaking the dried, powdered leaves in 70% ethanol for 7 days at room temperature. Then the extract was concentrated by evaporating ethanol using a rotary vacuum evaporator (N-N Series, EYELA, Tokyo, JAPAN) set at 60°C and 100 hPa" (Pichiah. 2012)

were even more pronounced, when we compare the effects on fatty acid oxidation (CPT-1), the PPAR-alpha and -gamma values.

Figure 2: Carnitine palmitoyltransferase I (CPT1), PPAR-alpha & -gamma activity and triglyceride & cholesterol content in the liver (left; expressed relative to rodents on normal chow). Histology of liver sections at 200x magnification for the different diets (Pichiah. 2012)

What's yet most striking is however that the liver - the organ that's so heavily involved in the etiology of insulin resistance - was virtually "fat-free" in the rodents who received the 1,000mg/day dose. The total triglyceride and cholesterol content was even lower than in the mice on the normal diet and the overall darker staining in the slices on the right of figure 2 is only further evidence of the beneficial effects the seabuckthorn extract had on the liver histology.

The effects of a 5% conjugated linoleic acid diet do actually resemble that of lipodystrophy, i.e. pathological fat loss and inability to store body fat. Strange, no? Well that's PPAR-gamma (read more).

PPAR-gamma? Wasn't that what you actually wanted to avoid? In a way this is right, since PPAR-gamma and even alpha are somewhat Janus-faced molecules (overview for PPAR-alpha). As beneficial as their expression in the liver may be, both inhibit the oxidation of glucose. PPAR-gamma is also involved in the maturation process from pre-adipocytes to mature adipocytes, increases lipogenesis in white adipose tissues, decreases the cell surface fatty acid transporter on muscle cells and increases glucose uptake in adipocytes (exclusively). All that is healthier than fat clogging your liver, but it's not exactly something that will make you leaner if you are work out and consume a junk-free diet.

In fact, the PPAR-gamma suppressing effects of the trans-10, cis-12 isomer of conjugated linoleic acid (CLA; cf. Kennedy. 2008) are actually what what produces such profound effects, as they were observed in the study I discussed on July 22, 2012 (see link beneath the image of the mice).

TTA and fish oil are potent antagonists of liver PPAR expression. With the uncoupling and anti-inflammatory effects of TTA being the key to unleash & maintain fat-burning (read more).

Bottom line: It appears as if the liver is - once again - emerging as a central player in "sick obesity", meaning being fat and sick and not just fat. Which reminds me of yesterday's post on Gluten and the development of metabolic disease, where fatness is no criteria, at all. The expression of the "liver cleansing" PPAR-gamma enzymes on the other hand was.

This in turn reminds me of the effects of fish oil and TTA (a pan PPAR-activator), which - despite their questionable use as a long-term intervention can in fact stimulate intra-hepatic fatty acid oxidation to levels which are so high that oxidation rates in and out of itself could bring about some problems.

Other nutritional factors you should take into account are choline (a deficiency will actually cause fatty liver disease; read more about choline) or taurine. And on the endocrine side of things you want to keep an eye on optimal DHEA levels (read more about its effects on PPAR-gamma), thyroid hormones, testosterone and estrogen (Nemoto. 2000).

References

• Kennedy A, Chung S, LaPoint K, Fabiyi O, McIntosh MK. Trans-10, cis-12 conjugated linoleic acid antagonizes ligand-dependent PPARgamma activity in primary cultures of human adipocytes. J Nutr. 2008 Mar;138(3):455-61.
• Nemoto Y, Toda K, Ono M, Fujikawa-Adachi K, Saibara T, Onishi S, Enzan H, Okada T, Shizuta Y. Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice. J Clin Invest. 2000 Jun;105(12):1819-25.
• Pichiah PB, Moon HJ, Park JE, Moon YJ, Cha YS. Ethanolic extract of seabuckthorn (Hippophae rhamnoides L) prevents high-fat diet-induced obesity in mice through down-regulation of adipogenic and lipogenic gene expression. Nutr Res. 2012 Nov;32(11):856-64.

Beyond Celiac: Study Sheds New Light on Obesogenic Effects of Gluten - Are PPARs & Bacteria Both Involved?

Cornflakes peanut butter cookies - guaranteed not gluten free ;-)

With Christmas Eve being over, and grandma's cookies, Christmas stollen, and all sorts of other stuff from the bakery in front of you (literally), Christmas Day may actually prove to be a way more "dangerous" than Christmas Eve - not just because of the total amount of calories, but also because of the low satiety effect of these sweet treats.

A recent paper by scientists from the Universidade Federal de Minas Gerais in Belo Horizonte in Brazil does now point to another reason you better give those bakery products a wide berth - not just, but especially with the energy overshoot on Christmas day: Gluten!

Study confirms for the first time what scientists and laymen alike have been speculating about

In what the scientists claim is the first well-controlled study of the effects of gluten intake on metabolic health in a non-celiac, but Western-style diet scenario, Fabíola Lacerda Pires Soares and her colleagues put two groups of C57BL/6 mice on identical, iso-caloric high fat (hypercaloric) diets that differed only in terms of the amount of gluten that was added to the chow (0% gluten vs. 4.5% gluten).

Interestingly, the gluten diet did not influence any of the usual suspects, like food intake, total fat-free mass, fecal lipids excretion, blood lipid profile, blood total protein and ectopic (liver and muscle) lipid concentration (if you look closely you will realize that the gluten-free group actually had higher TRIGs, although the difference did not reach statistical significance).

Figure 1: Usual suspects and closer look at the effects 8 weeks gluten supplemented vs. gluten-free diets had on serum markers of metabolic syndrome and visceral fat parameters (Soares. 2012)

The data in figure 1 (right) does yet also show that the gluten content of the diet did nevertheless have a significant impact on the total body mass, visceral fat mass, lipid content and most importantly the adipocyte size.

Figure 2: Absolute adipokine levels (left) and fasting glucose and insulin levels, as well as Homa-IR (Soares. 2012)

Add to that the blunted expression of the anti-inflammatory and anti-diabetic fat hormone adiponectin and the increased the >5x higher expression of leptin (figure 2). And mix that with the reduced expression of PPAR-alpha and gamma of which Soares et al. argue that they may well be the key factor in the detrimental modulatory effect the addition of gluten had on the visceral fat structure and the lowered expression of the fat liberating enzymes LPL and and HSL, as well as reduced levels of the fat burning proteins ACC and CPT-1 (figure 3).

Figure 3: PPAR-alpha, -gamma, LPL, HSL, ACC and CPT-1 expression compared to rodents on regular chow (left); crown like structures in stained slices from visceral fat, inflammatory markers TNF-alpha and IL-6 (Soares. 2012)

So, even if the initially mentioned blood markers (aka the usual suspects) would suggest that both the gluten-consuming and gluten-free rodents were similarly bad off, the profound difference in inflammatory markers within the adipose tissue and the presence of comparatively many necrotic and inflammatory adipocytes in the crown like structures stand in line with increases in HOMA-IR, fasting glucose and insulin and an already compromised glucose clearance which are well-known harbingers of the metabolic syndrome.

These observations do not simply shed a whole new light on a hitherto largely ignored contributer to the etiology of the metabolic syndrome, they do also show that one of the reasons it has not been identified before is an over-reliance on BMI, total fat mass and serum lipids in the early stages of diabesity.

Reardless of whether the gut microbiome is part of the mechanism by which gluten predisposes the development of metabolic syndrome. Eating more inulin- and beta-glucan rich foods like Jerusalem artichokes, agave, bananas, onion, steel cut oats, wild yams, yacon, etc. certainly won't hurt your efforts to get lean, stay lean and leave the role of the obese diabetic to the other (read more)

Bottom line: The study at hand provides a good reason to limit your intake of "healthy whole grains" and other gluten containing foods, regardless of whether you suffer from celiac or not. Whether the established detrimental effects of gluten on the integrity of the intestinal wall and the increased leakage of bacterially produced endotoxins from the highly unfavorably changes in the gut microbiome in response to the high fat diets (Hildebrandt. 2009) are part of, or even the primary cause of these observations still has to be elucidated. The same goes for strategies to counter the translocation of the endotoxins across the gut lining (cf. "Shedding some light on the leaky gut") and the dose response relationship between the total amount of gluten in your diet and its effects on your metabolism. With 7% of pure gluten, it goes without saying that you would basically have to live of wheat in order to get to anywhere similar amounts of gluten in the diet... that said: Is it possible that the effects occur only in the presence of the high fat diet? After all, this alone has been shown to favor a pro-inflammatory gut microbiome.

You see there are enough questions to be answered in 2013 and the SuppVersity is going to be the place you will read the respective answers first ;-)

References:

• Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, Keilbaugh SA, Hamady M, Chen YY, Knight R, Ahima RS, Bushman F, Wu GD. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology. 2009 Nov;137(5):1716-24.e1-2.
• Soares FL, de Oliveira Matoso R, Teixeira LG, Menezes Z, Pereira SS, Alves AC, Batista NV, de Faria AM, Cara DC, Ferreira AV, Alvarez-Leite JI. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem. 2012 Dec 17.

Conjugated Linoleic Acids: What's the Difference Between cis-9,11 and trans-10,12 CLA and Should We Label Them as "Transfats"? Plus: What Makes CLA Potentially Harmful?

If Hayden Panettiere drinks it dairy can't be bad - despite (or because?) CLA, right? Well, what if I told you that Mrs. Panettiere was advertising milk in the "Got Milk" campaign despite being lactose intolerant?

As a SuppVersity veteran you will be familiar with the idea that trans-10, trans-12 conjugated linoleic acid is the "fat burning" CLA isomer, while 9 cis,11 trans linoleic acid appears to blunt some of the pro-inflammatory actions of its cousin and has been shown to have specific physiological effects on it's own (e.g. increased bone health, cf. Platt. 2009; anti-cancer, cf. Corl. 2003).

As I already mentioned, this is probably nothing new for you, if you make sure to get your daily dose of SuppVersity wisdom everyday. What you may however not be aware of is the fact that researchers like Ye Wang and Spencer D. Proctor are - despite the never-ending hoopla around potential weight loss effects of CLA - still contemplating, whether CLA could not pose a major health threat to all or at least certain subgroups of the population and whether this should or shouldn't be reason enough to change the current food labeling practices.

Do we have to label CLA as "transfat"?

From a technical perspective the above question is obsolete. CLAs are transfats and would thus (technically, again) have to be labeled as such on the product label. From a health perspective, however, things do in fact look different. Due to the fact that the aforementioned ruminant (=naturally produced in the stomach(s) of ruminents) trans-fats have been associated with health benefits (Gebauer. 2011), we could effectively risk to scare consumers away from healthy foods if they were listed as part of the "transfat" category on the product labels.

What's actually the reason that one the same CLA isomer that will have you lose body fat will also "inflame" you? Due to the fact that most of the research on "fat loss supplements" is conducted in sick, obese individuals, people tend to get the false impression that "fat burners" were anti-inflammatory and that anti-inflammatory agents would burn fat.

Effects of 10-trans,12 CLA on fatty acids & glucose metabolism and IL-6 gene expression in isolated fat cells in the petri dish (Hartwig. 2013)

Now, while it is correct that soothing inflammation will help the future Mr. Average Joe, who is going to be an obese (pre-)diabetic, lose weight, this has little to do with any active contribution to the oxidation of body fat. 10-trans,12 CLA, on the other hand, has been shown to block lipid storage, increase mitochondrial uncoupling (UCP-2), lower PPAR-alpha and ramp up the oxidation and release of fatty acids from the fat stores (Hartig. 2013). Unfortunately it will also block the uptake of glucose and increase the expression of the pro-inflammatory cytokine IL-6 in fat cells. So, if you took 10-trans,12 CLA at very high doses it will probably in fact keep you lean.

If you cannot handle the sudden increase in free fatty acids, pack the glucose into your liver and muscle glycogen stores and deal with the exuberant amount of inflammatory cytokines, however, it will only make you sick.

Currently, the trans-fat content on many food labels (and in legislative documents) does not include ruminant CLA isomers and Wang and Procter acknowledge that:

"As highlighted in a recent quantitative review of prospective cohort studies by Bendsen et al. dietary consumption of ruminanttrans-fat may be protective against total as well as fatal CHD events." (Wang. 2013)

The researchers do however point out that concerns about potential adverse effect on atherogenic cholesterol profiles from supplemental CLA are not unwarranted - at least if they are used by a group of persons - abdominally obese and/or insulin resistant men, for example (Riserus. 2002 a,b).

Australia and New Zealand suggest a re-evaluation

Accordingly, Australia and New Zealand (FSANZ) proposed to re-evaluate their perception regarding the exclusion of CLA from the TFA definition on nutrition labels.

If you re-evaluate something, you do not necessarily have to change them and if you go through the concise summary of results Wang and Procter present in their paper (see table 1 for an overview of the currently published meta-analyses, it does not appear necessary to question the current practice to label only industrually produced trans fats.

Table 1: Meta analysis with beneficial (green), neutral (grey) and potentially negative outcome (red); based on Wang & Proctor (2013)

As the authors point out, the inclusion of CLA in the total amount of transfats on the label would only drive people away from the consumption of whole food products. This is particularly true in view of the fact that the ill-health effects of "trans-fats" are something everyone will have heard about. The fact that these ill health effects are not to be expected from trans fats in dairy and other CLA containing whole foods, on the other hand, is still news to many costumers.

Moreover, how would you, me and everyone else who may well be aware that CLAs are not the bad guys and the "trans-fat" in grass fat butter is not going to hurt us know if the 3g of transfats in another product we buy are actually from the undisclosed amount of butter (and thus CLA) in it? It could likewise be that the producer added a little extra partially hydrogenated vegetable oil to cut the product costs and neither you nor me would know that.

Suggested read: "A Higher Intake of CLA and Vaccenic Acid from Dairy, Beef, Veal and Lamp Could Prevent Subtle Weight Gain" | read more

Only the obese have to be worried: Based on the currently available evidence the healthy and lean person (hopefully you) has absolutely no reason to avoid products with a "high" natural CLA content and thus both the pro- (trans-10,12) and (partly) anti-inflammatory (cis-9,11) form of CLA in them.

For obese and insulin resistant individuals things do however look somewhat different. A 2004 study by Risérus et al., for example, has been able to show that even the allegedly "harmless", 9 cis,11 trans linoleic acid can worsen both lipid peroxidation and insulin resistance in 25 abdominally obese men. (Risérus. 2004).

With 3g/day the dosage that was used in the Risérus study, the amount of CLA was yet much hither than the amount of CLA you can possibly ingest with nourishing foods such as butter, full-fat dairy, grass-fed beef (and beef in general, by the way). Instead of these you are thus better advised to avoid CLA supplements... but don't worry if you take another look at the data in table 1 you will have to concede that they are pretty much useless, anyway.

Reference:

• Corl BA, Barbano DM, Bauman DE, Ip C. cis-9, trans-11 CLA derived endogenously from trans-11 18:1 reduces cancer risk in rats. J Nutr. 2003 Sep;133(9):2893-900.
• Gebauer SK, Chardigny JM, Jakobsen MU, et al. Effects of ruminanttrans fatty acids on cardiovascular disease and cancer: a comprehensive review of epidemiological, clinical, and mechanistic studies.Adv Nutr. 2011; 2, 332 – 354.
• den Hartigh LJ, Han CY, Wang S, Omer M, Chait A. 10E,12Z-conjugated linoleic acid impairs adipocyte triglyceride storage by enhancing fatty acid oxidation, lipolysis, and mitochondrial reactive oxygen species. J Lipid Res. 2013 Nov;54(11):2964-2978. 
• Lenz TL & Hamilton WR. Supplemental products used for weight loss. J Am Pharm Assoc. 2004; 44,  59– 67, quiz 67– 58.
• Onakpoya IJ, Posadzki PP, Watson LK, Davies LA, Ernst E. The efficacy of long-term conjugated linoleic acid (CLA) supplementation on body composition in overweight and obese individuals: a systematic review and meta-analysis of randomized clinical trials. Eur J Nutr. 2012 Mar;51(2):127-34.
• Platt I, El-Sohemy A. Effects of 9cis,11trans and 10trans,12cis CLA on osteoclast formation and activity from human CD14+ monocytes. Lipids Health Dis. 2009 Apr 29;8:15.
• Risérus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. Diabetes Care. 2002 Sep;25(9):1516-21.
• Risérus U, Basu S, Jovinge S, Fredrikson GN, Arnlöv J, Vessby B. Supplementation with conjugated linoleic acid causes isomer-dependent oxidative stress and elevated C-reactive protein: a potential link to fatty acid-induced insulin resistance. Circulation. 2002 Oct 8;106(15):1925-9
• Salas-Salvadó J, Márquez-Sandoval F, Bulló M. Conjugated linoleic acid intake in humans: a systematic review focusing on its effect on body composition, glucose, and lipid metabolism. Crit Rev Food Sci Nutr. 2006;46(6):479-88. Review.
• Schoeller DA, Watras AC, Whigham LD. A meta-analysis of the effects of conjugated linoleic acid on fat-free mass in humans. Appl Physiol Nutr Metab. 2009 Oct;34(5):975-8.
• Tricon S, Yaqoob P. Conjugated linoleic acid and human health: a critical evaluation of the evidence. Curr Opin Clin Nutr Metab Care. 2006 Mar;9(2):105-10. Review.
• Whigham LD, Watras AC, Schoeller DA. Efficacy of conjugated linoleic acid for reducing fat mass: a meta-analysis in humans. Am J Clin Nutr. 2007 May;85(5):1203-11.

Maintain & Increase Your Insulin Sensitivity - Wrap-Up: Overview + 3 Stacks. Plus: AMPK & PPAR-γ Revisited

It's not about exercise or nutrition, it's about both of them. And as long as it is not about the former it should not be about supplements either.

It's Sunday and finally time for the wrap up of the "Maintain & Increase Your Insulin Sensitivity" Series (read all previous installments). It took me quite some time to get through all the compounds on my and your list and the outcome is far from being a "complete" list of all the agents that can have beneficial effects on your insulin sensitivity. Still, if there is at least one agent, one fact or one take home message for each of the 6 previous articles of which you would say: "Ok, I guess that was worth wasting some of my valuable time on", I would be happy.

For myself it was by the way yet another occasion to learn more  about many of the agents, I reviewed in this series.

And if you listened to the SuppVersity Science Round-Up on Thursday, you will probably remember that I said that I was at least a cautiously excited about the potential of berberine... but I am wasting your time here. Let's start with the wrap up.

Lifestyle changes are more powerful than supplements: So don't forget that it's imperative to realize the lifestyle changes described in the first installment of this series. Otherwise the best you can hope to achieve with supplements (and drugs) is to slow the progression from insulin resistance to full-blown diabetes.

Before we take a look at the three stacks I have compiled, I do just briefly want to get you up to speed as far as the major underlying mechanisms of the supplements are concerned:

• AMPK: Some people in the medical establishment think of it as the good counter-part to mTOR. The fairy that will put an end to the pro-carcinogenic reign of the evil mTOR-witch, so to say. Others, who are mostly part of the "muscle head" community, think of AMPK as their fiercest enemy and mTOR as their brother in crime... It goes without saying that neither of these views is accurate. AMPK and mTOR are not even necessarily antagonistic - at least not for people like you - people who work out regularly. The mTOR expression after a workout does after all occur in the presence of increased an expression of AMPK. What else could you possibly ask for, if you want to "recomp" (i.e. lose fat and gain muscle to improve your physical appearance)?
  
  

  

  Few people know that there are two different iso-forms of AMPK. The alpha-2 isoform is the one that's expressed during a workout and it works hand in hand with mTOR and not against it (learn more)

  What may at first look like a paradox is actually easily explained if we don't look at the characteristic downstream effects of mTOR and AMPK, but rather at the circumstances in which they are activated. Outside of the previously mentioned exercise context those are in fact antagonist. With mTOR being triggered by the abundance of nutrients - specifically protein, and even more specifically leucine - you would not expect to see increases of AMPK at the same time. The latter is after all, expressed, when a cell senses a lack of nutrients in form of an increase in ADP (~used ATP) and a decrease in ATP levels. The reaction, i.e. an increased expression of AMPK will then have downstream effects on the uptake of glucose and the oxidation of fatty acids, both of which contribute to a restoration of normal ATP levels in the cell.
  
  Both AMPK and mTOR act highly localized. The exercise induced glucose uptake is thus muscle-specific - that should be obvious, since exercise will raise the ADP levels only in the muscle. Supplemental agents that mimic this effect, on the other hand, act systemically. Agents like alpha lipoic acid will therefore increase glucose uptake in both muscle and adipose tissue (Moini. 2002). After a workout and at other time points, where the glucose uptake is already high and, more importantly, muscle specific, it is thus not necessarily the best idea to try to "escalate" the effects by using a class of supplements that is often mislabeled as "insulin mimetics". 
• A note on the PPAR-effects of CLA, fish oil, TTA & co: I guess as a well-read SuppVersity reader you will know that CLA is a supplemental non-starter. In human studies the outstanding results from rodent trials have never been successfully replicated. This could be - at least in parts - a result of the dosage and the ratio of t10c12 CLA to it's c9t11 counterpart, which has the exact opposite effects on the PPAR-gamma receptor (Toomey. 2005).
  

  

  Some of you will probably also remember my articles about the pertinent effects of TTA and fish oil in the. Of those only the latter has a significant PPAR-gamma activity. TTA, on the other hand is predominantly a PPAR-delta and -alpha agonist and thus more a "true fat burner" than a general "fat handler", which is probably the best way to describe fish oil (learn more).
  PPAR-gamma: If you listened to the Science Round-Up last Thursday you will have heard me say that blocking PPAR-gamma will inhibit the storage of energy in the adipose tissue. That's true, but by no means as beneficial as you may be thinking. It is, for example, pretty likely that the CLA induced PPAR-gamma blockade is also responsible for the increased propensity to develop non-alcoholic fatty liver disease in CLA fed rodents.
  
  The results Fedor et al. present in a 2012 paper, show that these effects can be ameliorated if the PPAR-gamma suppressor (i.e. trans-10, cis-12-conjugated linoleic acid) is combined with a supplement that exerts the opposite effects in the liver - a supplement you all know pretty well: DHA, as in "fish oil". It is, just like many of the "older" diabetes drugs, an (allegedly less) potent PPAR-G agonist (=activator; cf. Neschen. 2006).
  
  Whether the blockade of PPAR-gamma is a good or a bad thing does thus obviously depend on the scenario we are talking about. For the lean individual, who is working out regularly and wants to defend his leanness in the absence of (un-)wanted eating orgies and "mass building regimen" it is probably a good thing. He or she will not have an energetic surplus that could end up clogging up the liver. And while the same goes for the average obese individual who has finally gotten his act together, PPAR-gamma inhibitors would seem clearly counter-indicated for sedentary individuals on the high calorie, high sugar, high fat diet so many people consider "normal", these days.
  
  As paradox as it may seem, the anti-diabetic effects of PPAR-gamma activating thiazolidinediones (TZDs) which are still used to "treat" (I should rather write "manage") diabetes mellitus and other diseases that feature insulin resistance will thus come at the expense of increased body fat storage. The latter can be pretty pronounced,as the data from pre-diabetic individuals Bray et al. published only recently goes to show you (figure 1).
  
  Despite their anti-inflammatory effects and their (limited) use in highly inflamed type II diabetics you will therefore not find any of the herbal PPAR-gamma agonists like pomegranate, pumpkin, mellisa officinalis, morus alba, artemisia capillaris, bitter melon, guggul, banaba or mulberry (cf. Huang. 2009) in the stacks below. And that despite the fact that they have anti-inflammatory activities.

Ok, I guess you are either fed up of theoretical details by now, or were so before and just scrolled down to the "stacks" in the first place.

There is a reason there is no "athlete's stack" here: Since I know you will be asking, I thought I will say it right away. The reason that there is no "athlete's stack" in the list is that athletes are either "normal-weight insulin resistant" or they are insulin sensitive and don't need any supplements on top of the lifestyle changes from episode I. You got your workouts, folks: There is no better muscle specific insulin sensitizer out there! If you are looking for agents to stay lean try berberine, it's anti-ppar-gamma effects may help and if you want more, stack it with taurine, of which you should by now know that its benefits go well beyond "glucose sensitizing" / You don't? Well, then take a look at the previous articles about taurine.

I guess I will not make you wait any longer, then... I have come up with three scenarios, the "insulin resistant obese / overweight individual", "the normal-weight insulin resistant individual" and the "cheater" (explanations follow below the stacks):

• 

  Table 1: List of the most important supplements discussed in the series; more details on each of them, as well as on those I did not include in this overview can be found in the individual installments.

  The insulin resistant obese / overweight individual will have to target weight and fat loss and increases in insulin resistance; a stack that could facilitate all three would contain.
• ALA (or metformin) - 3x 300-500mg 
• Berberine - 3x 200-400mg
• Fucoxanthin - 3x 5mg
• Taurine - 3x 2-3g
• Chromium - 1x 200mcg (*)
• The normal-weight insulin resistant individual will have to take care of inflammation, (usually) a beginning fatty liver and not taking the next step to the obese diabetic.
• Berberine - 3x 200-400mg 
• Chlorogenic acid - 3x 200-300mg
• Taurine - 3x 2-3g
• Milk thistle - 3x 200-400mg
• The cheater can be either of the former or a healthy perfectly insulin sensitive individual who wants to reduce the sudden rise in blood glucose after a meal.
• Cinnamon - 1-6g (Ceylon cinnamon)
• Vinegar - 2x tablespoons
• Green tea - 1-2 cups

The insulin resistant obese / overweight individual needs relieve most urgently, therefore he will also trial fucoxanthin, which has some impressive, but not exactly reliable weight loss data. He will either have a script for metformin or will use alpha lipoic acid (ALA) as a substitute and he will make sure that he gets adequate chromium by taking 200mcg of chromium picoliante or niacin-bound chromium per day *if this is not already in a multi he or she is taking.

The normal-weight insulin resistant individual has slightly different needs than his overweight comrade. He or she is almost certainly suffering from chronic inflammation and beginning or existing NAFLD (the obese will have that, as well, but for him it's only part of the problem). With it's effects on both AMPK and PPAR-gamma berberine will make sure that the body fat levels remain low. Just like taurine (read more), chlorogenic acid (Panchal. 2012) and milk thistle (read more), it will also help "revive" the liver and sooth the inflammation by promoting the bodies own antioxidant defense system.

The cheater, on the other hand, could be everyone who wants to undo (or fore-do, if you will) a high GI carb meal. The ingredients of this stack will ameliorate the blood sugar response and could thus potentially reduce any damage you could do to your pancreas... but let's be honest. With the occasional cheat you are not going to do any damage and if cheating becomes common practice you violate the "lifestyle-changes first!" principle and won't get away healthily no matter how much supplements you take.

Browse previous articles:

Lifestyle Changes

ALA, GABA, Taurine & Co.

Berberine, Banaba & Co.

Cinnamon, Curcumin & Co.

Lemon, Starch, Coffee & Co.

Chlorogenic acid, fucoxanthin & Co.

References:

• Fedor DM, Adkins Y, Mackey BE, Kelley DS. Docosahexaenoic acid prevents trans-10, cis-12-conjugated linoleic acid-induced nonalcoholic fatty liver disease in mice by altering expression of hepatic genes regulating fatty acid synthesis and oxidation. Metab Syndr Relat Disord. 2012 Jun;10(3):175-80.
• Huang TH, Teoh AW, Lin BL, Lin DS, Roufogalis B. The role of herbal PPAR modulators in the treatment of cardiometabolic syndrome. Pharmacol Res. 2009 Sep;60(3):195-206.
• Moini H, Tirosh O, Park YC, Cho KJ, Packer L. R-alpha-lipoic acid action on cell redox status, the insulin receptor, and glucose uptake in 3T3-L1 adipocytes. Arch Biochem Biophys. 2002 Jan 15;397(2):384-91.
• Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline GW, Sono S, Gillum M, Shulman GI. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes. 2006 Apr;55(4):924-8. 
• Panchal SK, Poudyal H, Waanders J, Brown L. Coffee extract attenuates changes in cardiovascular and hepatic structure and function without decreasing obesity in high-carbohydrate, high-fat diet-fed male rats. J Nutr. 2012 Apr;142(4):690-7.
• Toomey S, Harhen B, Roche HM, Fitzgerald D, Belton O. Profound resolution of early atherosclerosis with conjugated linoleic acid. Atherosclerosis. 2006 Jul;187(1):40-9. Epub 2005 Sep 22.

The Quest For the Best N6:N3 Ratio. Swine Study Suggests: 5:1 is Healthy, 1:1 Will Also Cut Fat and Build Muscle

 Yes, this study is about omega-3s, but it is not about the beneficial effects of fish oil.

Ok, I see you are totally excited, so I am not going to beat around the bush for long: According to a soon-to-be-published study from the Hunan Provincial Engineering Research Center of Healthy Livestock, Institute of Subtropical Agriculture at the Chinese Academy of Sciences  a 5:1 ratio of n-6:n3 (as in omega-6 to omega-3) is good enough to keep pigs healthy.

Kicking out another couple of grams of omega-6 fatty acids, on the other hand, had pretty intriguing effects on the body composition of the ninety-six male cross-bred (Large White£
Landrace) pigs who happened to weigh about as much as an average human being (another advangate, of swine - HED calculations are not necessary; learn more).

Did you know that pigs are opportunistic omnivores just like us and provide a better model of human metabolism than our little, furry remote cousins with the big round eyes and the long tails who are populating the laboratory cages of scientists all around the world (cf. Miller. 1987)?

Lineseed or soybean - that makes all the difference

I hope you did not already start popping fish oil, while you are reading this. After all, in this case the glorified residual waste from the fishery industry did not contribute to either the health or weight loss benefits Duan et al. observed in their pigs who were fed one of the four isoenergetic diets with n6:n-3 PUFA ratios of 1:1, 2·5:1, 5:1 and 10:1 for 2 months.

Table 1: Ingredients, nutrient and fatty acids composition of the diets the pigs received; † vitamin premix (Duan. 2013)

As the ingredient profiles of the different diets (table 1) tell you the major source of omega-3 fatty acids was lineseed oil. The latter is basically devoid of long-chain omega-3 fatty acids (EPA & DHA). Instead, it contains the short-chain variety aka alpha-linolenic acid that is often laughed at in the health and fitness community as being the useless precursor to the powerful "fish oils" EPA and DHA (note: the level of DHA was identical in all diets!).

So, no fish oil, just ALA

Although the allegedly more potent LC-PUFAs were missing, the changes in body composition and the overall improvement (=reduction) of the activity of the potentially pro-carcinogenic PI3K-alpha gene and the fat storage genes FATP-1 and PPAR-gamma (learn more about PPAR-gamma) were still impressive.

If you take a closer look at the data in figure 1, though, you will realize that the effects on body composition require a reduction to 2.5:1, better 1:1 to become significant.

Figure 1: Feed conversion rate, muscle mass, adipose tissue mass, lean to fat mass ratio expressed relative to the levels of the pigs in the 5:1 n6:n3 group after 2 months on the different diets (Duan. 2013)

At the same time there is a clear relationship between increased adiposity and the amount of soybean oil in the pig diets. Thank god that the USDA in their incredible wisdom lists it among the top dietary sources for fat *sarcasm*.

Ah, I'd better not get political here, but let me point out one thing: In view of the currently available scientific evidence it borders physical injury resulting from negligence that the "guidelines" do not put an emphasis on the reduction of the the crazily high n-6:n-3 ratio of the Standard American Diet (16-17:1).

---

Unlike this pig study, a previous rodent study suggests you should pick EPA over DHA over ALA for weight loss purposes (learn more)

Bottom line: This is one of the most convincing well-controlled animal studies we have that would support that the purportedly "paleolesque" 1:1 ratio of n-6:n-3 fatty acids entails highly significant health benefits,  even if those omega-3 fatty acids don't come from fish, but from lineseed oil.

One thing we must not forget, though, is the fact that the beneficial changes in health and body composition were brought about by the concomittant reduction in omega-6 and increase in omega-3 fatty acids. Simply drinking a bottle of lineseed or cod liver oil everyday could thus do more harm than good, because with ~3g of oil per 100g the diet was also low in total fat and almost devoid of saturated fats and whether the same results would occur in a high fat scenario is beyond what the study at hand can tell us.

References:

• Duan Y, Li F, Li L, Fan J, Sun X, Yin Y. n-6:n-3 PUFA ratio is involved in regulating lipid metabolism and inflammation in pigs. Br J Nutr. 2013 Aug 15:1-7. [Epub ahead of print]
• Miller ER, Ullrey DE. The pig as a model for human nutrition. Annu Rev Nutr. 1987;7:361-82. Review.

Ephedra is Back! 'Mahabala', Featuring PEA, Ephedrine, Choline, Betaine & More, Is Nature's Hypolipidemic, Anti-Diabetic and Cardioprotective Fat Burning Stack

Image 1: Sida rhomboidea
leafs contain ephedrine and
other fat loss related alkaloids
(Tan Hoard Exports)

If you are a supplement producer, I suppose you will soon drop me an email to get the phone number of Ranjitsinh V. Devkar from the Division of Phytothrapeutics and Metabolic Endocrinology at the Department of Zoology of the M. S. University of Baroda in Gujarat, India. And, I must admit, if I had not always believed that "Nature knows best!", I would probably have been similarly surprised as some of you will have been, when they read the title of this blogpost - the 'ingredient profile' of Sida rhomboidea (also Sida rhombifolia), or  "Mahabala", a weed that is found in marshy places all across India and that has been used in Ayurvedic medicine for centuries to treat fever, heart disease, ever, heart diseases, burning sensations, urinary disorders, piles and all kinds of inflammation, looks like it had been printed on a non-FDA-approved (and thus potentially effective ;-) fat burner.

Figure 1: Alkaloid content of Sida rhomboidea extract (data adapted from Prakash. 1981)

If you have been following the exponential growth of the supplement market and the allegedly creative ideas the supp-designers had as far as fat burners were/are concerned, you will notice that, vasicinol and vasicinone aside, all the alkaloids, as well as choline and betaine Prakash et al. found in an extract from 5kg of Sida rhomboidea sound vaguely familiar.

Figure 2: Chemical structure
of the alkaloid vasicinone
(extracted from seeds of
Peganum Nigellastrum
by Zhang. 2009)

Vasicinol, vasicinone? What is that? Despite the fact that there is not much reliable data on the pharmacology of vasicinol and vasicinone, the two less well-known alkaloids in Sida rhomboidea, the available scientific data and information on their traditional use in Ayurveda suggests that these compounds, which are also present in other Ayurevedic herbs, exhibit hyopglycemic, as well as weak anti-acetylcholinesterase (Zhang. 2009) and bronchodilatory (Amin. 1959) effects. All three of these, which entail lower blood sugar levels, increased levels of acetylcholine and beta-adrenergic activity (which is the most likely explanation for bronchodilatory effect of the alkaloids), could synergistically help facilitate weightloss.

In view of this potent 'ingredient profile', it is no wonder that the addition of 1% of this natural fat loss wonder to the hypercaloric high fat diet (+58% more energy than low fat chow) of male C57BL/6J mice (6–8 weeks of age) staved off >25% of the 20-week weight gain (cf. figure 3) the unsupplemented HFD group experienced with respect to a low fat fed control group in the most recent of a whole series of rodent studies, Devkar et al. have conducted over the course the last years (Thounaojam. 2011).

Figure 3: Weight [in g] of mice during 20 weeks on control, high fat (HFD) and high fat diet with 1% Sida rhomboeidea extract (data adapted from Thounaojam. 2011)

From a health perspective, it may yet be even more important that the Mahabala supplement also prevented the "HFD induced increment in [...] plasma lipids and leptin, visceral adiposity and adipocyte hypertrophy" the scientists had observed in the unsupplemented group. The authors attribute these effects to the down-regulation of PPARγ2 and leptin gene expression that went hand in hand with an attenuation of food intake in the C57BL/6J mice.

Image 2: Mice on low fat (A), high fat (B)
and high fat diet + 1% Sida rhomboeidea
extract after 20 weeks (Thounaojam. 2011)

The decline in food intake, the scientists had already observed in previous studies , makes it quite difficult to give a definite number on the absolute amount of Sida rhomboeidea extract the mice consumed on a daily basis. It ranges from 25mg at the beginning of the study to ~13mg at the end and would translate into a human equivalent dose of 2mg/kg and 1mg/kg of Sida rhomboeidea extract per day. If the simple mathematical calculation that is solely based on the ratio of body surface to weight would suffice to reliably translate data from a rodent model to humans, an 80kg human being would thus have to consume somewhere between 80mg and 160mg of Mahabala per day to see similar effects.

Now, you may argue that, after all, this "wonder extract" turns out to be just another appetite suppressant. Yet, while Mahabala did affect the appetite of the laboratory animals, its profound in-vitro effects on pre-adipocytes differentiation and leptin release, as well as the previously mentioned changes in PPARγ2 and leptin gene expression, the scientists observed in the rodent model, suggest that the primary mechanisms for Mahabala's preventive effects against weight and fat gain (-56% less abdominal fat, -46% less epidididymal fat) is unrelated to the reduction in food intake.

Figure 4: Effect of Sida rhomboeidea extract (SR) and Rosiglitazone (ROS) on insulin tolerance in C57BL/6J mice after 16 weeks on low fat (LFD) or high fat diet (HFD) containing 1% (SR1) or 3% (SR2) SR or  0.05% ROS (data adated from Thounaojam. 2010)

Add to that its profound (as potent as the anti-diabetes drug Rosiglitazone) effects on insulin sensitivity (cf. figure 4) the researchers had observed in a previous study (Thounaojam. 2010) and remind yourself of the fact that not ephedrine, but its foolish and unnecessary abuse / overconsumption were responsible for the unfortunate deaths of a handful of people, the majority of whom had preexisting health problems (yes, being severely overweight is a health problem), and you will probably agree with Ranjitsinh V. Devkar and his colleagues who conclude that their findings "validate the potential application of SRLE as a therapeutic agent against obesity". And, if you asked me, I bet that it won't take long until you see the first Mahabala supplements hit the highly competitive fat loss market - despite the fact that an ephedrine-containing Ayurvedic herb probably ain't FDA compliant ;-)

CLA For Weight Loss: Safe, but Ineffective. Conjugated Linolic Acid Fails to Improve Body Composition or Lipid Profile in 8-Week Human Study

The early 2000s were the fat years: "Want to lose fat? Eat fat!" became the credo of more and more nutritional gurus, who put their faithful clients "on" EFAs, PUFAs and a certain fatty acid (FA) that, despite, or rather due to its presence in our food chain, had hitherto received little attention by the medical orthodoxy: conjugated linoleic acid (CLA). All of a sudden, this "unhealthy" trans-fatty acid that can be found in relatively large amounts in high fat milk products, was supposed to become the magic bullet in every dieter's fight against unhealthy or unaesthetic body fat.
So, is the majority of the Americans in the 21st century going to be obese, simply because they are not consuming enough CLA? A recent study from Canadian scientists (Jones. 2011) suggests otherwise.

In a 3-phase crossover trial, Jones et al. recruited 27 overweight (BMI ≥ 25 kg/m²), borderline hypercholesterolemic [LDL-cholesterol (C) ≥ 2.5 mmol/L] men aged 18–60 y, who consumed during three consecutive 8-wk phases (with a 4-wk washout period between each trial) either 3.5 g/d of safflower oil (control) or a 50:50 mixture of trans 10, cis 12 and cis 9, trans 11 (c9, t11) CLA:Clarinol G-80, and c9, t11 isomer:c9, t11 CLA.

Figure 1: Chemical structure of the 2 isomers of conjugated linoleic acid (CLA)
and the unconjugated form linoleic acid (LA)
(image from Kent. 2007)

Body weight, body fat, and lean body mass (all reliably measured by DXA), CLA's effects on fatty acid oxidation, as well as blood lipid profiles and safety biomarkers, including insulin sensitivity, blood concentrations of adiponectin, and inflammatory markers (high sensitive-C-reactive protein, TNFα, and IL-6) and oxidized-LDL were assessed at the beginning and end of each trial. The results were unimpressive:

Compared with the control treatment, the CLA treatments did not affect changes in body weight, body composition, or blood lipids. In addition, CLA did not affect the β-oxidation rate of fatty acids or induce significant alterations in the safety markers tested.

Or, in other words, CLA supplementation @ 3.5g/day did not produce any of the favorable effects potential customers are promised by the advertisements of an industry that thrives on the hopes of overweight of millions of obese individuals world-wide.

A conclusive evaluation of both the effectiveness, as well as the safety of CLA would require further studies using and comparing the effects of different  mixtures of the different CLA isomers that  have been found to exert very different metabolic effects - with the trans-10, cis-12 isomer having a more pronounced effect on PPAR-gamma induced metabolic changes (Hermann. 2009) and more compelling evidence of possible negative side effects, such as increased oxidative stress (Risérus. 2007).

So, after all. The verdict on CLA is still out there! And you know: The SuppVersity is the place, where you will hear about future research first.

Amorfrutins: Plant-Derived Selective PPAR-Modulator Outperforms Regular Diabetes Drug and Exhibit Significant Weight Loss, Insulin and Leptin Sensitizing Effects

Image 1: Amorpha fruticosa (photo R. Ott) is a deciduous shrub growing to 4.5 m, the fruits of which contain about 500mg of amorfrutins per 1kg raw material.

One major argument I have been bringing forward against the use of diabetes "medications" for quite some time, now, is that most of them are not "treatment" strategies, in the sense that they help people lose body fat to naturally restore insulin sensitivity and get off their drugs, but rather the opposite. Drugs like rosiglitazone, for example, allow for the further expansion of the adipose tissue and reduce blood glucose levels by storing the excess glucose in those new or expanding fat cells. A recent paper by Weidner et al. does now suggest that there may be a natural alternative (Weidner. 2012), which - despite acting on the same PPAR pathways lacks the fattening effects of synthetic PPAR-gamma ligands (molecules in drugs that interact with the peroxisome pro-liferator-activated receptor gamma) - lacks those highly undesirable fattening effects of thiazolidinediones.

Glycyrrhiza foetida & Amorpha fruticosa amorfrutins - the future of blood sugar management?

With the so-called "amorfrutins" from the edible parts of the two legumes Glycyrrhiza foetida (roots) and Amorpha fruticosa (fruits), the former being related to the "licorice plant" Glycyrrhiza glaba and the latter a brush that is native to the east of the USA, a group of scientists from Germany and the UK have thus identified yet another potent plant-component that outperforms its synthetic competition pretty easily.

Figure 1: Body weight (in g; left) and phosphorylated / non-phosphorylated PPAR-gamma (data from densitometric analyisis) of diet-induced obese mice on high fat diet (HFD) + placebo (vehicle), HFD + rosiglitazone or HFD + amorfrutin 1 (data adapted from Weidner. 2012)

Administered at a dosage of 100mg/kg per day (human equivalent 8mg/kg), the amorfrutins, which have a 2x higher binding affinity for the PPARγ receptor (236 to 354nM) than the aforementioned diabetes drug rosiglitazone (aka Avandia, one of the commonly prescribed thiazolidinediones), had a much more favorable effect on the phosphorylated to unphosporylated PPAR-gamma ratio and lead to statistically highly significant reductions in body weight over the 23-day supplementation period (cf. figure 1).

A note on the significance of PPAR-gamma phospohorylation: The phosphorylation of the peroxisome proliferator-receptor gamma is associated with a profound dysregulation of a large number of genes whose expression is altered in obesity. Its prevention is thus currently regarded as one of the most promising treatment strategies for insulin resistance; one that comes without the negative side-effect of increases in body weight for which all the other thiazolidinediones are notorious. It is therefore not surprising that the blockade of the phosphorylation of PPAR-gamma by amorfrutin 1 (the one denotes the first of the 4 amorfrutins the biological activity of which was investigated in the study) was "significantly correlated with improved insulin sensitivity" in the study at hand (Weidner. 2012).

Other than in most synthetic selective PPAR-modulators, such as bezafibrate, for example, the weight loss was also not mediated by a reduction in food intake, but, as Weidner et al. speculate, a direct results of an increase in energy expenditure - a hypothesis that would certainly be supported by the slight, yet likewise statistically significant increase in thyroid hormone concentration (T4) in the amorfrutin group:

Because the complex effects of PPARγagonism on various endocrine systems and downstreamphysiological changes (e.g., change in thermogenesis, fatty acid oxidation, or activity) are not fully understood, it is difficult to probe all potential mechanisms by which the amorfrutins may affect weight regulation. For example, recent studies suggest that complex interaction of brain PPARγ-signaling with peripheral organs may contribute to the physio-logical regulation of energy balance (30, 31). Presumably, the amorfrutins as partial agonists may act on neuronal PPARγby an-tagonising diet-derived endogenous agonists such as fatty acids, thereby leading to relative weight loss.

Against the background that we are apparently dealing with the PPAR equivalent to SERMs (selective estrogen receptor modulators such as clomid or tamoxifen) and SARMs (selective androgen receptor modulators), it appears prudent to mention that Weidner et al. did not find any cross-activities with other receptors, such as the estrogen receptors alpha and beta, the liver x receptor alpha, the constitutive androstane receptor, and the pregnane receptor. Cross-reactions like these are quite common with other xenobiotics (exogenous substances with biological effects that are produced by other organisms) and can lead to unexpected and mostly undesirable side effects (e.g. anti-androgen activity).

Leptin resistant? No problem for amorfrutins!

Contrary to rosgliatazone, the amorfrutins work their antidiabetic magic even in the presence of full-blown leptin resistance. While the former does not just fail to reduce, but actually promotes weight gain in leptin receptor-deficient db/db mice, treatment with amorfrutin 1...

[...] had no significant effects on mouse body weigh [... but] reduced plasma insulin concentrations more strongly than rosiglitazone (36% vs 19% decrease after 24 d) . Amorfrutin 1 treatment also decreased plasma concentrations of glucose, triglycerides, and free fatty acids. Possibly as a result of enhanced insulin sensitivity, amorfrutin 1 also appeared to prevent deterioration of pancreatic function in insulin-resistant mice, as pancreatic insulin levels improved compared to nontreated control mice.

In genetically non-disadvantaged, normal diet-induced obese mice (DIO) and thus purportedly in most obese humans, treatment with amorfrutin 1 lead to identical reductions in the areas under the glucose and insulin curve in an intraperitoneal insulin sensitivity test (IPIST; is similar to an oral test, but the injection into the intraperitoneal cave ensures that 100% of the glucose actually hits the blood stream) and reduced the basal leptin levels to the same extend as rosiglitazone did (cf. figure 2).

Figure 2: Areas under the glucose and insulin curve in an intraperitoneal insulin sensitivity test (left), basal leptin levels and photographs of the livers of the diet-induced obese mice at the end of the 24-day study period (data and images adapted from Weidner. 2012)

Despite almost identical i improvements in insulin and leptin sensitivity,u>only the amorfrutins, not the thiazolidinedione, rosiglitazone, were able to reduce the diet-induced triglyceride accumulation in in the liver of the treated animals (cf. figure 2, upper right corner) and could thusly help prevent, maybe even revert non-alcoholic fatty liver disease; an effect, by the way, that may be ascribed to

• an increase of the PPAR-alpha dependent purported "anti liver-fat" co-factor Tbl1, and
• reduced inflammation in both the liver, as well as the white visceral adipose tissue of the rodents.

In the end, it does thusly come down to the usual suspects, inflammation + insulin resistance and while the amorfrutins from the roots of a certain variety of licorice (Glycyrrhiza foetida) and the fruits of an American shrub (Amorpha fruticosa) share their ability to reduce the former and increase the latter, they don't to it at the expense of further increases in body and organ fat and could therefore help to actually resolve - not just manage and perpetuate - the current diabesity epidemic.

"When are we going to see those amor-thingies on the market?"

Image 2: Amorfrutilean could be a weight loss adjuvant that works.

Yet while they could, just as their inferior, since fattening synthetic counterparts, rosiglitazone (Avandia), pioglitazone (Actos) & co be combined with metformin (which works via a totally different mechanism), it appears questionable that the next generation of Avandamedm which combines metformin and rosiglitazone in one pill, is going to have amorfrutins in it. Not because we still need human trials (which is obviously the case), but rather due to the fact that no pharma company will be willing to pay those trials, when the outcome, a "drug" based on a naturally occurring substance that is easily extracted from a common plant, would not be patentable and may seriously compromise the sales of their current "antidiabetic" (actually I should write "pro-obesity") drugs.

If independent future human trials were yet able to confirm the previously discussed results, I am still pretty confident that we are soon going to see the supplement industry jumping aboard. With Amorfrutiburn, Amorfrutilean or Amorfrutibol being the most likely candidates for the BB.COM topselling "fat burners", weight loss adjuvants or "nutrient partitioners", respectively. And you know what, combined with a couple of lifestyle changes, this stuff could actually work - at least  for the chubbier one's among the soon-to-be physical culturist. Whether leaner folks or even bodybuilders will benefit to the same extend does yet remain to be seen.

BCAA Ward Off Body Fat Gain on Hypercaloric High Fat Diet: Branch-Chained Amino Acid Feeding Triggers Favorable Metabolic Changes in Diet-Induced Obese Mice.

When it comes to BCAA products,
stick to the basics. There is a reason nature
has them in the 2:1:1 ratio.

Science is more and more beginning to realize that the oversimplified "calories in vs. calories out" concept is hardly able to explain weight gain and loss in the ever-increasing number of obese individuals throughout the world. The findings of a relatively recent study from Oita University, Japan (Arakava. 2011) underline the importance of a paradigm-shift in nutritional counseling from dietary advice that is based on caloric value towards concepts accounting for the different signaling cascades various macro- (protein, fats, carbohydrates) and micro-nutrients (vitamins, minerals, polyphenols, etc.) trigger.

What the scientists found was that mice, who were fed a hypercaloric high fat (45%) diet for 6 weeks, gained significantly less weight, if their drinking water was enriched with BCAAs in the course of the last 2 weeks.

The BCAA-treated group gained almost 7% less body weight and had less epididymal adipose tissue (WAT) mass than the control group (p<0.05). BCAA supplementation also reduced the hepatic and skeletal muscle triglyceride (TG) concentrations (p<0.05).

The reason for this "anti-obesity" effect of BCAAs, the scientists speculate, is the increase of hepatic PPAR-alpha and uncoupling protein (UCP) 2, and PPAR-alpha and UCP3 in the skeletal muscle, respectively. While the upregulation in PPAR-alpha would be responsible for the reduction in blood (& muscle) triglycerides (other than total cholesterol a reliable risk factor of heart disease & diabetes), the increases in uncoupling protein (put simply) render the mitochondrial wall more permeable for protons and thus increases the dissipation of energy as heat. In consequence of these BCAA-triggered adaptations, the mice spent more energy and "burned" more fat.

Figure 1: Glucose, Insulin, Triglycerides and Free Fatty Acids in Control and BCAA treated DIO mice
(data adapted from Arakava. 2011)

If you have a closer look at the data I plotted in figure 1 you will further notice that a) the decrease in serum triglycerides is only modest (note: the decrease in liver triglycerides may be of greater importance, anyways) and b) BCAA supplementation also had a direct effect on insulin secretion, the reduction of which may well contribute to the reduced fat accumulation Arakava et al. observed in the BCAA group.

Despite the fact that applicability of the results of rodent studies to human beings (and I am referring to thermogenic effects, in particular) is still questionable, the take home message of this study is to look into the physiological effects of individual nutrients rather than into their energy equivalent in calories to evaluate their use and usefulness in weight loss and weight gain (remember BCAAs are a promising adjunct to cancer therapy and other conditions associated with muscle loss and/or wasting, as well, cf. Tazi. 2010).