Zinc: 15mg Are Plenty - After 120 Days Rodents on Diets Containing 2xRDA of Zinc Develop Metabolic Syndrome

Image 1 (scipop): Physicists and battery specialists know that copper and zinc make a galvanizing couple. If you put too much copper into your "battery" it will however stop working.

A recently published study from the Panjab University in India clearly suggests that doubling or quadrupling your zinc intake, a common practice in the health and fitness community, could do more harm than good. After only 4 months on a low phytate, high zinc diet (2x or 4x more zinc than in the standard chow), the rodents in the medium and high zinc intake goups showed a couple of unsettling metabolic changes (Taneja. 2013):

• 20-40% increase in food intake
• 20% increased body weight
• 2x or 2.7x elevated blood sugar
• 3.75x or 6x elevated insulin levels
• 100% increase in cortisol
• 2x or 2.5x elevated leptin levels

In short, while the Wistar rats that consumed the basal diet with the "rodent RDA" of 20mg zing per kg diet (0.53mg/day, 1mg/kg; HED ~0.17mg/kg or 8014mg/day) those with a two (human equivalent: 30mg) or four times (HED: 60mg/per) higher intakes developed all the classic symptoms of the metabolic syndrome

• insatiable hunger despite overabundant energy intake
• uncontrolled weight-gain => obesity
• high blood sugar, insulin resistance => type II diabetes
• constantly elevated cortisol levels
• leptin resistance

Interestingly, these highly undesirable effects of long-term were precipitated by profound morphological changes in the structure of the mucosal epithelial cell layer of the intestine:

Figure 1: Mean microvillus height and number/unit surface area of mucosal epithelial cell of intestine in normal zinc (control) or high zinc groups (Taneja. 2013)

The TEM studies of intestinal segment revealed a significant increase in the absorption surface area of the absorptive mucosal epithelial cells. It was reflected as increase in mean height and number/ unit surface area of the microvillus (figure 1). Their mean height (nm) was calculated as 506.1 ± 2.30 in control group-I, 749 ± 1.22 in group-II and 942 ± 1.30 in group-III. Their  number/unit surface area (µm) was found to be 10.4 ± 0.51 in group-I, 13.2 ± 0.33 in group-II and 15.4 ± 0.36 in group-III (figure 1).

The increases in height and number/unit surface area were suggestive of increased capability of the intestine to absorb the nutrients per unit area than the control group-I.

Now what is interesting about these observations is not just that it is 100% logical (at least for a physicist like me) that an increase in epithelial surface area will increase the nutrient absorption, but also that scientists knew about them and their beneficial side-effects in people with Crohn's disease, a damaged  or "leaky" gut all along (Sturniolo. 2001) and still nobody ever even thought about the downsides of subsequently increased nutrient assimilation. Instead, it was once again simply concluded that what helps the sick, obese and pre-diabetic cannot hurt normal people - and that despite the absence of ample evidence for consistent beneficial effects of  zinc supplementation as a protective, let alone curative means in sick people (Beletate. 2007), or zinc (+ magnesium) supplementation in athletes (Wilborn. 2004)

Double or quadruple your zinc intake, avoid phytates and turn from athletic to diabetic!?

Figure 2: After only 120 days the rodent in the high zinc groups exhibited all the typical symptoms of the metabolic syndrome (Taneja. 2013)

In view of the fact that still way too many gymrats adhere to the false belief that a zinc supplement (just like a "high performance" multivitamin) was an absolute staple supplement everybody striving to build a better physique should consume, it is no wonder that supplement vendors like to put copious amounts of this cheap ingredient into their products. Even if you are cheap (or smart) and avoid buying one of the "performance" multis, the 15mg of zinc every standard multi has plus the 30-50mg of your "nightly" ZMA, would take you right into the danger zone and even beyond and assuming that you follow another currently often proffered advice, which is to avoid phytate containing foods like a plague, your additional dietary zinc intake would probably get you right into the 60mg/day zone, which was so detrimental to the metabolic health of the rodents in the Tenja study.

In the defense of zinc supplements it should yet be mentioned that the chow the rodents were fed in the course of the experiment was not exactly what you, as an educated SuppVersity students would consider healthy, let alone "optimal". After all the diet was deliberately composed of "semi-synthetic" ingredients such as refined sucrose instead of the regular "grainy" pallets you would find in standard rodent chow, "to rule out the possibility of Zn-interaction with fibres and phytates" (Taneja. 2013), so that it would not take so long for the effects of the exuberant zinc intake to manifest.

"But my ZMA works! I feel so much better on it and if I drop my multi I get sick!"

"Artificial diet, rodent study, no real world implications", I hear ya! A 2004 study by Xiang et al. is yet only one out of many examples which suggest that you should not be so sure that will get away with taking your zinc-laden "staple supplements" (and in the case of the "multi" not just because of the zinc) for years: Increased lipid oxidation after 2 weeks, and increases in total cholesterol, triglycerides, LDL-C, ApoB100 and decreased in HDL and ApoA1 after 8 weeks of 50mg zinc per day in formerly healthy men are likewise clear indices of developing metabolic syndrome (Xiang. 2004). A result, by the way, that does not stand in contrast to studies on the effects of dietary zinc intake on glucose management such as Kanoni et al. (2011), where the highest dietary zinc intake of all subjects was 12.4mg (!) and thus still below the RDA and right on par with what the "average" American gets from his junkfood diet and supplements (see figure 3)!

Figure 3: I would not hope that you are eating like the "average American", are pre-diabetic and / or obese, but the data from the NHANES study is another puzzle to the picture that explains why Mr./Mrs. Average's health may benefit, while yours may suffer from supplemental zinc - they just don't get enough in their diet (Briefel. 2000)

If you are not constantly wreaking havoc on your gut lining and want it to regrow, are obese or diabetic (we do have some studies that suggest that at least in certain subgroups supplemental zinc can ameliorate this condition, yet mostly at the expense of higher insulin levels), you may want to reconsider if those staples of yours are really necessary, at least beneficial or maybe detrimental to the way you look feel and perform. And in the, as the guy at your local supp store would probably say, "totally improbable" case that despite taking all the staples he recommended, your blood glucose levels are getting out of whack, your cortisol is skyrocketing and your HDL is plummeting towards zero, you better not take his advice that all that will resolve once you introduced the latest (R-)ALA based nutrient partitioner into your supplement regimen (cf. "Lean & Muscular With Alpha Lipoic Acid?" ;-)

References:

1. Briefel RR, Bialostosky K, Kennedy-Stephenson J, McDowell MA, Ervin RB, Wright JD. Zinc intake of the U.S. population: findings from the third National Health and Nutrition Examination Survey, 1988-1994. J Nutr. 2000 May;130(5S Suppl):1367S-73S.
2. Beletate V, El Dib RP, Atallah AN. Zinc supplementation for the prevention of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005525. Review. 
3. Kanoni S, et al. Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis. Diabetes. 2011 Sep;60(9):2407-16.
4. Taneja SK, Jain M, Mandal R, Megha K. Excessive zinc in diet induces leptin resistance in Wistar rat through increased uptake of nutrients at intestinal level. J Trace Elem Med Biol. 2013 Jun 8.
5. Sturniolo GC, Di Leo V, Ferronato A, D'Odorico A, D'Incà R. Zinc supplementation tightens "leaky gut" in Crohn's disease. Inflamm Bowel Dis. 2001 May;7(2):94-8.
6. Wilborn CD, Kerksick CM, Campbell BI, Taylor LW, Marcello BM, Rasmussen CJ, Greenwood MC, Almada A, Kreider RB. Effects of Zinc Magnesium Aspartate (ZMA) Supplementation on Training Adaptations and Markers of Anabolism and Catabolism. J Int Soc Sports Nutr. 2004 Dec 31;1(2):12-20. 
7. Xiang Y, Yang X, Bian J, Wang L. [Effects of high level Zn intake on metabolism in man]. Wei Sheng Yan Jiu. 2004 Nov;33(6):727-31.

19x Increase in Growth Hormone 60min After Ingestion of 1g of Glycerophosphocholine (GPC) in Young Male Subjects

Image 1: Don't worry one thing is sure - GPC won't give you a gut like that ;-)

A couple of days ago, I have written about the exorbitant choline consumption of some of bodybuilding legends, Randy Roach writes about in his Muscle Smoke & Mirrors Vol. II  and to be honest, I was quite surprised that among the many responses I got, none broached the issue of the latest and greatest supplemental choline spin-off: Glycerophosphocholine, or short GPC - a supposedly superior, because fat-bound (hence "glycero" as in "glycerol) and highly bioavailable bean-derived form of choline. Whatever the reasons may be, I suppose you still won't mind to hear that a recent experiment that was conducted at the Faculty of Sport and Health Science of Ritsumeikan University in Shiga, Japan, yielded quite interesting results with respect to the endocrine and metabolic short-term effects of 1,000mg of GPC in 8 healthy male (25+/1y) subjects (Kawamura. 2013).

19x more growth hormone 60 min after the ingestion of 1,000 mg GPC, ...

And no, the subheading above does not contain a typo, at least not in the number, which is "nineteen" as in +1800%, which was, as the data in figure 1 shows, the average increase in serum growth hormone concentration exactly 60 minutes the lean subjects (11% body fat) experienced after ingestion of the GPC caps compared to placebo (the study was double-blinded and randomized, there was a period of two weeks in-between the testing days).

Figure 1: Fatty acid metabolism (left), choline levels (middle) and growth hormone levels (right)  6min0 and 120 min after the ingestion of placebo pills or 1,000mg glycerophosphocholine (Kawamura. 2013)

It is unquestionable the data in figure 1  looks pretty impressive. Yet not all changes are in fact statistical significant (I marked them by adding the relative differences between active and placebo arm) and as exciting a growth hormone spike of +1800% may sound, the subsequent drop to levels below the placebo arm should remind you, a seasoned SuppVersity veteran of the futility of supplemental "growth hormone secretagogues", such as arginine, leucine, a combination of both etc.; they all share a fundamental weakness - after each spike there is a huge trough.

...but just  6.88x more GH production over 2h

And therefore it should not really surprise you that we have the 2-h AUC, i.e. the area under growth hormone curve, a measure for the total amount of growth hormone that is released in the course of the timespan for which the AUC was measured, was "only" 6.88x larger after the ingestion of the glycerophasphatecholine supplement, than after placebo(cf. figure 2).

Figure 2: 2h AUC for free choline, free fatty acid, 3-hydroxbutyrate (ketones) and growth hormone after the ingestion of 1,000mg GPC; data expressed relative to placebo control (Kawamura. 2013)

Still, even this obviously transient increase in growth hormone in the fasted that occured in response to the +38-51% increase in circulating plasma choline went hand in hand with profound increases in free fatty acids (due to the lipolytic effects of GH; cf. Marcus. 1994) and ketone bodies, which is a sign of increased fatty acid metabolism must be a good thing,... right? It would appear so, but without answering the following two fundamental questions "How does it work?" and "What does that mean", we will be having a hard time to justify this conclusion. After all, the ingestion of 4mg/kg caffeine have been shown to illicit a >500% increase in free fatty acids (FFA) after only 40min in trained subjects (LeBlanc. 1985) and still none of the caffeine laden "fat burners" with other ingredients, which further augment the lipolytic effects of caffeine will actively burn body fat.

So what's the mechanism of action? And what does it tell us about the real world implications?

The working principle Kawamura et al. suggest is actually quite straight forward: With increasing serum choline levels, the influx of choline into the brain will increase as well. This will augment the synthesis of acetylcholine, which, in turn, has been found to decrease the concentration of somatotropin release-inhibiting factors right at the hypothalamic level and thus disinhibit the production of growth hormone (Blusztajn. 1983). Put simply: Somewhere down the line the increase in serum choline will pull the breaks that keep your body from producing growth hormone.

A note to all the stim-junkies out there: I guess, you will be intrigued (or shocked?) to hear that blocking the catecholamine induced stimulation of the a2-adrenergic receptor with yohimbine has been shown to negate the aforementioned growth hormone promoting cascade. And that irrespective of whether you try to augment it by supplements or just want to keep your natural rhythm intact (Minamitani. 1989). The first real-world implication would thus be "don't take your GPC alongside alpha-2 antagonists such as yohimbine" (better not take those at all ;-)!

Now this raises the question does that matter? With arginine and lysine, we already know that it doesn't, but maybe we just have a larger effect size here? To answer the last question first - the spike is in fact spectacular and way above the average response to the long-touted GH boosters arginine, lysine or glutamine, which ranges from "no effect at all" (Carlson. 1989) over 4.5x (Welbourne. 1995) to the whopping 13x increase in response to an intravenous injection of  0.5 g arginine/kg (Tanaka. 1991). If do yet take another look figure 2 you will notice that I inserted a quote from Kawamura et al.'s discussion of the results into the graph - a quote that is of paramount importance to quantify the real world significance of these ostensibly HUGE increase in GH (which you will certainly see referenced by respective supplement manufacturers in their glossy marketing material, very soon):

"The GPC-induced increases in GH levels observed in this study were of a comparable degree to the increase induced by moderate-intensity exercise"

I guess, you don't need me to tell you how "effective" popping a couple of those pills is thus going to be compared to training and diet alone in furthering your muscle gains and fat loss. And in terms of overall and cardiovascular health, you should already know from my previous blogpost, "Old School Supplements: Choline  Faster, Stronger, Leaner & more Muscular" that regular dietary choline as in eggs, meats, fish, leafy greens, etc. will do just as fine.

How much choline do you need? According to Coates et al. plasma choline concentrations can double after a 2-egg meal (~225mg choline) by up to two-fold (Coates. 2005). That would effectively be more than what we see as peak increase in the study at hand. And certainly puts the "need" for supplemental choline into perspective. The LD50, i.e. the purportedly fatal dosis, after the ingestion of which 50% of the subjects would die, is "of the order of 200-400g" (Gilman. 1980) - an amount of choline your tummy probably would not hold o to long enough to be absorbed, anyway ;-)

And in the unfortunate case that you do believe that you are running short of choline, because you don't eat all the good choline containing foods out of ethical or whatever other reasons, and thus insist on supplementing, I suggest you yourself a 500g container of choline bitartrate powder (don't let that become wet, though! It will stink like rotten fish ;-). Those 500g of choline bitartrate (40% choline, 60% tartate) will cost you about as much as 60x300mg caps of the overpriced GPC and has been "scientifically proven" (not in supplement company terms, but in SuppVersity terms) to safely increase circulating and brain choline levels and its metabolites after oral ingestion, as well (Stoll. 1996; Babb. 2004). And let's be honest, even if the effects on growth hormone were GPC specific - even on the boards, people have meanwhile realized none of those arginine + lysine GH boosters does make a difference and not because they would not produce transient increases in GH, but simply because those are physiologically meaningless and mostly compensated for in the course of 24h.

References:

1. Babb SM, Ke Y, Lange N, Kaufman MJ, Renshaw PF, Cohen BM. Oral choline increases choline metabolites in human brain. Psychiatry Res. 2004 Jan 15;130(1):1-9.
2. Blusztajn JK, Wurtman RJ. Choline and cholinergic neurons. Science 1983;221:614–20.
3. Coates, P.M., Blackman, M.R., Cragg, G.M., Levine, M., Moss, J., White, J.D. (Ed), Encyclopedia of Dietary Supplements. Marcel Dekker, New York, NY. 2005. p. 108. . 
4. Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co. Inc. 1980. p. 1575. 
5. Carlson HE, Miglietta JT, Roginsky MS, Stegnik LD. Stimulation of pituitary hormone secretion by neurotransmitter amino acids in humans. Metabolism 1989;38:1179
6. Kawamura T, Okubo T, Sato K, Fujita S, Goto K, Hamaoka T, Iemitsu M. Glycerophosphocholine enhances growth hormone secretion and fat oxidation in young adults. Nutrition. 2013 Jun 5. 
7. LeBlanc J, Jobin M, Côté J, Samson P, Labrie A. Enhanced metabolic response to caffeine in exercise-trained human subjects. J Appl Physiol. 1985 Sep;59(3):832-7.  
8. Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B, Bendavid E, Saynina O, Salpeter SR, Garber AM, Hoffman AR. Systematic review: the effects of growth hormone on athletic performance. Ann Intern Med. 2008 May 20;148(10):747-58. Epub 2008 Mar 17.
9. Marcus C, Bolme P, Micha-Johansson G, Margery V, Brönnegård M. Growth hormone increases the lipolytic sensitivity for catecholamines in adipocytes from healthy adults. Life Sci.1994;54(18):1335-41.
10. Minamitani N, Chihara K, Kaji H, Kodama H, Kita T, Fujita T. Alpha 2-adrenergic control of growth hormone (GH) secretion in conscious male rabbits: involvement of endogenous GH-releasing factor and somatostatin. Endocrinology 1989;125:2839–45.
11. Stoll AL, Renshaw PF, De Micheli E, Wurtman R, Pillay SS, Cohen BM. Choline ingestion increases the resonance of choline-containing compounds in human brain: an in vivo proton magnetic resonance study. Biol Psychiatry. 1995 Feb 1;37(3):170-4. 
12. Welbourne TC. Increased plasma bicarbonate and growth hormone after an oral glutamine load. Am J Clin Nutr 1995;61:1058

Lean & Muscular With Alpha Lipoic Acid? You Could Be Just as Lean, But More Muscular W/out "Nutrient Repartitioner"!

Image 1: Lean enough? Ever thought it may be better to stop taking your ALA, now?

I know what you are probably thinking right now: "Not yet another rodent study on the insulin sensitizing effects of alpha lipoic acid!" And in fact, you would be totally right if the results of this very study, which is going to be published in the next issue of the European Journal of Nutrition could not just save you a lot of money but also propel, or rather restore your lean mass gains. After all, the real-world implications of the differential effects of alpha lipoic acid supplementation Prieto-Hontoria et al. observed in lean vs. obese rodents would suggest that your expensive "nutrient repartitioner" may repartitions the energy away from your muscles and thus impair your gains. Put simply: Alpha lipoic acid keeps you lean, yeah... lean, but probably undermuscled!


Now you are listening, right? 

Well, let's see what the Spanish researchers did, then. Basically Prieto-Hontoria and his colleagues repeated an experiment many other researchers have conducted before. They took a bunch of young male Wistar rats and fed them a...

• regular diet with a macronutrient ratio of 20/67/13 (protein, carbs, fats)
• regular diet + 0.25g racemic alpha lipoic acid per 100g chow
• high fat diet with a macronutrient ration of 20/20/60 (protein, carbs, fats)
• high fat diet + 0.25g racemic alpha lipoic acid per 100g chow

And while the existence of a ALA control group on a normal diet alone would be a very welcome twist on your average "lipoic acid helps vs. diet induced insulin resistance / obesity"-study, the existence of two pair-fed groups

• regular diet, pair-fed receiving the same amount of chow as the regular diet + ALA group consumed voluntarily, but without the ALA content
• high fat diet, pair-fed receiving the same amount of chow as the high fat + ALA group consumed voluntarily, but without the ALA content

Allows for unique conclusions in terms of which effects are actually ALA-mediated and which ones are nothing but a side-effect of the anorexic (=appetite / food intake reducing) effects of alpha lipoic acid.

What's good for obese pre-diabetics on the standard American diet ...

Body weight and food intake were recorded every 2–3 days. And blood glucose, insulin, HOMA-IR, white adipose tissue mass, body total body weight gain, serum adiponectin levels and AMPK levels in white and brown adipose tissue, as well as skeletal muscle were determine at the end of the 8-week experimental period.

Figure 1: Effects of 8 weeks of supplemental alpha lipoic acid on body composition of rodents on different diets; active treatment vs. control (left) and active treatment, pair-fed (with active treatment) and control (right; data based on Prieto-Hontoria. 2013)

If you take a look at the left graph in figure 1 you see, what you probably would have expected. The rodents in the ALA groups (ad-libitum fed) gained significantly less body weight and had significantly less body fat than their peers, regardless of which diet they were on. Ok, the "lean mass" (here simply the difference between total and fat mass and thus not necessarily 100% identical to muscle mass - the rodents in the ALA groups could for example also have lower bone or organ weights) is lower, but alas, at least they are lean! And you are right, lean they are, but their pair-fed peers in the regular diet group, who received the exact same amount of food, but without any supplemental alpha lipoic acid, were exactly as lean, but made significantly greater gains (cf. figure 1, right)!

... can be detrimental for healthy, lean individuals whose ideal body image is not just skinny!

Figure 2: AMPK expression in white & brown fat and muscle (top, based on Prieto-Honta. 2013), and implications (bottom)

Now that we know about beneficial effects for SAD dieters and the detrimental effects for physical culturists, it's about time to take a look why on earth this happens and the answer - as counter-intuitive as that may sound, is via downregulation of AMPK (click here to read my dissertation on the "mTOR <> AMPK Seesaw ") - yes, you heard me right. As it turns out the "beneficial" effects of ALA on 5' adenosine monophosphate-activated protein kinase activity are tissue- and downstream effects diet-specific. Therefore, the detrimental effects of the decreased skeletal muscle and brown adipose tissue AMPK activity are outweighed by the increase in white adipose tissue AMPK activity, the researchers observed in ALA supplemented rodents from both groups, was outweighed by the increase in white adipose tissue AMPK activity (and increases in adiponectin, see figure 2) only in the high fat diet group. The rodents who received the normal chow, on the other hand, achieved a much more favorable body composition by simply mimicking (obviously through pair-feeding and not voluntarily) the ALA induced (small) reduction in food intake.

"Hold on, what's all that AMPK b*s* about? Where's the connection to being lean & muscular?"

The downregulation of BAT AMPK activity, on the other hand, is as the analysis of the role of AMPK in cold thermogenesis by Mulligan et al. suggests, is a clear downside of ALA (Mulligan. 2007) and could in fact be related to its previously reported negative effects on thyroid metabolism, respectively the conversion of the "inactive prohormone" T4 to the metabolically active T3 (Segermann. 1991). Likewise, the reduction of skeletal muscle AMPK is not a benefit as the data in figure 1 clearly shows that the bro-scientific claims about muscle loss due to increased skeletal muscle AMPK activity don't hold. Something that should actually be obvious, in view of the role AMPK plays skeletal muscle glucose uptake, glycogen and ATP regulation (Kurth-Kraczek. 1999; Musi. 2002), and mitochondrial biogenesis (Hardie. 2010).

Figure 3: Insulin, HOMA-IR, adiponectin and adiponectin relative to white adipose tissue weight in control, pair-fed (same food intake as ALA, but no supplement) and ALA supplemented rodents after 8 weeks (based on Prieto-Hontoria. 2013)

Still, due to the profound increases (total and relative to fat weight) in adiponectin (cf. figure 3), a fat-derived hormonal with well-established insulin-sensitizing and anti-obesity effects (Yamauchi. 2001; Shehzad. 2013), which showed a statistically significant correlation (after correction for adiposity) with the HOMA index, a recognized marker of insulin resistance, and its preventive effects against diet induced obesity, alpha lipoic acid should remain among the recommended supplements for obese, insulin resistant or diabetic subjects.

Is alpha lipoic acid for you? If you are lean, this study says "NO"!

Image 2: If you are the fat endo at the bottom, ALA could be for you. If you are the guy on the left, mild cutting and bulking w/out ALA is for your. And if you are on the right, you better spend your money on protein, creatine, BC/EAAs.

Its merit for lean physically active people, who consume a energetically appropriate whole-foods diet and strive to build a lean and muscular, not just a skinny physique, its usefulness is yet somewhat questionable. After all, the pair-fed animals had an equally low amount of body fat as their peers on ALA, but statistically significant more lean body mass; and I personally don't believe that it is a realistic assumption that these effects could be countered by simply eating more without having negative effects on the total amount of body fat you would accumulate on this heavy-duty bulk.

Your best bet would to try and "exercise away" the negative effects on  skeletal muscle AMPK expression, but let's be honest: Would you rather wear a helmet instead of simply stopping to hammer your head against the wall? You would, ha? In that case you are beyond help, I guess... go ahead then and do what works for your obese neighbor.

Note (I know someone is going to ask this): If anyone can show me peer-reviewed in-vivo data that confirms the constantly made claim that the physiological effects (not the petri-dish or XYZ-essay effects) of R-ALA are superior, not just on a gram-per-gram base, but qualitatively, tho those of the cheap and obviously less profitable racemic ALA (= natural mix of R- and S-ALA), I would be inclined to answer the question "wouldn't taking R-ALA maybe make a difference".

References:

• Hardie DG. Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc. 2011 Feb;70(1):92-9. Epub 2010 Nov 11.
• Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999 Aug;48(8):1667-71.
• Mulligan JD, Gonzalez AA, Stewart AM, Carey HV, Saupe KW. Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse. J Physiol. 2007 Apr 15;580(Pt. 2):677-84.
• Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002 Jul;51(7):2074-81. 
• Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Martínez JA, Moreno-Aliaga MJ. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr. 2013 Jun 5. [Epub ahead of print]
• Segermann J, Hotze A, Ulrich H, Rao GS. Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels. Arzneimittelforschung. 1991 Dec;41(12):1294-8.
• Shehzad A, Iqbal W, Shehzad O, Lee YS. Adiponectin: regulation of its production and its role in human diseases. Hormones (Athens). 2013 Jan-Mar;11(1):8-20. 
• Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001 Aug;7(8):941-6.

Cold Thermogenesis - A Safe Ephedra Alternative? 70kcal Increase in 24h Energy Expenditure is Negligible, 50% Lower Than Ephedrine, Not Likely to Occur Obese or Older People

Image 1 (odditycentral): Jin Songhao, one of China’s most seasoned icemen and not exactly as lean as you may expect based on what you currently read around the blogosphere, managed to beat the previous world record for the longest ice bath - 120min! Congrats, Jin!

Ephedrine for years the go-to OTC fat burner for physique athletes and average Joe's and Jane's alike is no longer (officially) available: No matter how bold the label claims about X mg of "ephedra extract" may be - NONE(!) of the currently available "ephedra based" over-the-counter (OTC) fat-burners contains significant amounts of the active alkaloids, which made the old Mua huang based herbal ephedra products so effective. Against that background, dieters are constantly on the look-out for novel "gimmicks" to help them finally get rid of those annoying love-handles. One of those gimmicks, which has caught quite some attention as of late, is called "cold thermogenesis" and revolves around the idea that our bodies should consume more energy to keep a normal body temperature in a cold, compared to a normal temperature environment.

How is that different from a "thermogenic fat burner"

The most obvious difference between cold thermogenesis and "thermogenic fat burners" is actually so straight forward that I hardly dare stating that the former is induced by exposing yourself to low(er than normal) temperatures, while the promise of the latter is that the various ingredients of currently or formerly available OTC "fat burners" will induce a thermogenic response, irrespective of the current ambient temperature.

Figure 1: Antropomorphic data of the study participants (Cypess. 2013)

The results of a recently published study from the the Boston Harvard Medical School does yet provide somewhat more sophisticated insights into the differences between cold exposure and a sympathomimetic (i.e. an activator of the sympathetic nervous system), such as ephedrine. On three separate, independent study visits that took place in random order the ten healthy volunteers (age 27.1 years) who participated in the study (see figure 1 for DEXA based anthropometric data) and had been fasting since 12am the day before were exposed to one of the following "stimuli":

• ephedrine - a single intramuscular dose of 1mg/kg ephedrine
• saline control - an equal volume of saline
• cold exposure - in a surgeon’s cooling vest (Polar Products) w/ water temperature 14 °C

60min after the injection of ephedrine, saline, or the initiation of cold exposure, the change in metabolic rate was measured and blood was drawn to determine several metabolic and endocrine markers. Another 60min later, PET-CT scanner images (cf. figure 2, right) to quantify BAT mass and activity were taken. Since the participants obviously had to get rid of their cooling vests for this procedure, the total cold exposure time was limited to 120min, so that it is questionable how valid the 24h energy expenditure calculation (cf. figure 3) actually is. After all, it is not very likely that the norepinephrine levels would constantly stay at 200% over baseline (cf. figure 2).

Figure 2: Metabolic and endocrine effects (expressed relative to saline) of ephedrine injection and cold exposure (main image); CT scans with green arrows in the combined scans indicating  the principal cervical, supraclavicular,
and thoracic depots of BAT (Cypess. 2013)

As far as the acute phase is concerned, it is yet quite obvious that both cold exposure and ephedrine elicited statistically significant effects on various metabolic and endocrine parameters. The exact nature and the purported mechanism that is responsible for these metabolic and endocrine effects are however very different for both treatments:

• while ephedrine lead to an increase in blood glucose (probably subsequent to increased glyconeogenesis), cold exposure did not 
• while ephedrine lead to significant increases in lactic acid levels (corresponding to increases in glucose + glucose oxidation), cold exposure did not
• while ephedrine lead to profound increases in β-hydroxybutyrate (increased ketone productions from fat), cold exposure did not
• while ephedrine increased serum non-esterified fatty acid (NEFA) concentrations (due to increased lipolysis), cold exposure did not
• while ephedrine elevated insulin production (probably due to stress induced insulin resistance), cold exposure did not (p = 0.29)
• while ephedrine lead to highly significant (p < 0.001) increases in C-reactive peptide, cold exposure elicited "only" significant elevations (p = 0.005)
• while ephedrine produced already highly significant increases in noripenephrine levels, those were even more pronounced upon cold exposure
• while ephedrine lead to statistical significant increases in thyroid hormone Total T3 (+14%, p = 0.026) and Free T4 (+19%, p = 0.014), cold exposure did not
• while ephedrine lead to a profound (-22%) and statistical significant (p = 0.007) drop in ghrelin ("hunger hormone" and metabolic regulator), cold exposure did not

In conjunction with the combined CT scans from figure 2 these differences clearly indicate that contrary to ephedrine, which is a mere sympathomimetic (put simply a potent "stim" ;-) without depot-specific (here brown adipose tissue) thermogenic effects, mild cold exposure (remember: those were no ice-baths!) has the ability to stimulate brown adipose tissue (BAT) energy expenditure without significant systemic effects on heart rate or thyroid hormone metabolism.

What does that mean? Is GNC soon going to carry cooling vests instead of fat burner pills?

If you read the scientists' rave conclusion that "[i]n contrast to ephedrine [...] mild cold exposure stimulates a specific response by the SNS [sympathetic nervous system] to activate BAT and increase energy expenditure with few other metabolic effects" and their subsequent reference to the "obesity and diabetes pandemics" and the demand for "safe and novel treatments" of the latter, it is quite understandable that people who are referred by their gurus to "scientific evidence" like this are willing to believe that "cold thermogenesis" would help them to finally get rid of their beer-, burger- and burrito-bellies.

Figure 3: Increase in 24h energy expenditure (kcal/day, left) and detectable BAT volume (right; Cypess. 2013)

If you do yet take a look at the actual metabolic effects (cf. figure 3) the 2x more pronounced effect of ephedrine on 24h energy expenditure (+140kcal/day vs. 70kcal) confirms what my previous overview of the metabolic and endocrine effects of ephedrine and cold exposure already suggested: Ephedrine does not simply have more "side effects" it is also more effective.

Figure 4: Activity of BAT activity in relation to body fat levels (van Marken Lichtenbelt. 2009)

Important:  One thing the scientists wink at in both the abstract as well as the conclusion are the profound inter-individual differences in terms of detectable BAT volume and activity. While the median volume of detectable brown adipose tissue in men and women was 22mL and 20mL, respectively, there was one female subject with a BAT mass of 190mL (85x over median!), one with 7ml and one woman without any detectable brown adipose tissue. Similarly, the BAT mass in the men ranged from 46mL to 12mL. Both the existence of individuals without any significant amounts of metabolically active body fat, as well as the observation of high inter-personal variability in the study at hand stand in line with previous results of Saito et al. who found a ratio of 15/32 (45%) non-responders in young (23-35y) and 22/24 (92%!) in older (38-65y) subjects (Saito. 2009). And as if that alone would not render the practical value of cold exposure as a means to battle the "obesity and diabetes pandemic" questionably enough, van Marken Lichtenbelt et al. report that exactly those people for whom ephedrine and other sympathomimetics such as sibutramine would actually pose a non-negligible health risk, i.e. obese and metabolically deranged people, don't just have 40% less brown adipose tissue, but also a -76% reduced BAT activity (van Marken Lichtenbelt. 2009; cf. figure 4). The implications of these findings should be obvious: It is a) by no means certain that sitting in a non-heated room, let alone an ice-bath, is not just going to give you a cold, but even if it works it is b) probably not going to make a difference for those people who need it most - I mean, let's do the math: "70kcal/day minus 76% of the former equals 16.8kcal per day"!

That being said, even the profoundly greater total increase in energy expenditure in the ephedrine group is of a "magnitude" (I would write "minitude" if such a word existed) that would be completely negligible if it were not for the bad and "dangerous" sympathostimulating side effects (Andraws. 2005), which will allow you to train longer, to diet harder (Astrup et al. ascribe 75% of the weight loss effect due to the ingestion of the infamous ECA stack to anorexia, i.e. loss of appetite; cf. Astrup. 1992) than any ice-filled bathtub in the world will ever do.

Skip on ice-baths, stop winning about the ephedra ban. Get your diet & workouts in check!

Image 2: I don't think Francine Sablan, IFBB Figure Pro and like Adelfo one of Myotropics' sponsored athletes, uses the air-conditioning, let alone a funky cooling vest or ice-baths to propel her fat loss. And why would she? She loves working out and she has her diet in check ;-)

I know this is not going to be a popular conclusion, but believe me, the additional +70kcal/day you could expend in the cold, if you are one of the lucky non-obese "responders" (see red box above), won't make you lose a single pound. Even the "good old" ECA stack (remember: the Cypess study used intravenously administered ephedrine; hence, the effect sizes are directly comparable with pertinent studies from the late 1980s and 1990s using orally administered herbals) worked its fat burning magic only, when it was combined with a comprehensive diet and exercise protocol - and in those scenarios it was mostly the influence of its sympathostimulating activity on your ability to adhere to your diet and to endure the hardships of strenuous workouts and not its often-touted and largely overestimated "thermogenic" effects (cf. Astrup. 1985; Astrup. 1992) that were mostly responsible for the larger-than-life results, people are still raving about.

References:

1. Andraws R, Chawla P, Brown DL. Cardiovascular effects of ephedra alkaloids: a comprehensive review. Prog Cardiovasc Dis. 2005 Jan-Feb;47(4):217-25. 
2. Astrup A, Bülow J, Madsen J, Christensen NJ. Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am J Physiol. 1985 May;248(5 Pt 1):E507-15.
3. Astrup A, Toubro S, Christensen NJ, Quaade F. Pharmacology of thermogenic drugs. Am J Clin Nutr. 1992 Jan;55(1 Suppl):246S-248S.
4. Cypess AM, Chen YC, Sze C, Wang K, English J, Chan O, Holman AR, Tal I, Palmer MR, Kolodny GM, Kahn CR. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci U S A. 2013 Jun 4. 
5. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009 Apr 9;360(15):1500-8. Erratum in: N Engl J Med. 2009 Apr 30;360(18):1917.
6. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009 Jul;58(7):1526-31. Epub 2009 Apr 28.

Mono-Sodium Glutamate (MSG), NAFLD, Leptin Resistance, Trans-Fats, HFCS, Gluttony, Leaky Gut & Brain, the Vagus Nerve and the Chinese Restaurant Syndrome - Bon Appetit!

Image 1 (msg-exposed.com): Is obesity the inevitable, unnatural metabolic long-term equivalent of the dreaded "Chinese Restaurant Syndrome"?

Earlier today, I posted a blurb from a recently published epidemiological study on the effects of mono-sodium glutamate, aka MSG, an umami = all taste receptor activator that is commonly found in all sorts of ready made foods that would otherwise taste as lame as their individual fake ingredients, on the SuppVersity facebook wall (Insawang . 2013). The scientists had evaluated the data from 324 families (349 adult subjects, age 35–55 years) from a rural area of Thailand and found that the prevalence of metabolic syndrome was not just significantly higher in the tertile with the highest MSG intake, but that the "odds ratio", i.e. the chance that a certain parameter, in this case "obese, yes/no" would be found to be true, increased with every 1 g increase in total MSG intake irrespective of  the total energy intake and the level of physical activity.It took roughly 2 minutes for the first sharp-witted "SuppVersity student", in this case that was Wyatt Brown, to spot that post and ask what I believed could explain this observation.

Honestly, I had not really thought about that before, but simply assumed that the effects were probably mediated via not yet fully elucidated effects of dietary glutamate on the balance of excitatory and inhibitory neurotransmitters... after thinking about that for a moment I realized that in the absence of hyperphagia (i.e. extreme hunger and subsequently higher caloric intake), which was obviously not the case for the obese Thais with high MSG intakes, this explanation was not really satisfactory.

Does it all come back to food quality once again?

My next thought was that this could yet again be an issue of food quality vs. food quantity. After all, junk food and all sorts of foodstuff that's made with tons of food-additives to disguise their inferior, nutrient-poor and thus "tasteless" ingredients are the most likely candidates with respect to the MSG exposure in the Western and Eastern "developed" *rofl* world are concerned. In view of the fact that "diet quality" was (as so often) not among the variables Insawang et al. had assessed, their study did not allow for any conclusions in this respect, so that I had to dig deeper and came up with a couple of interesting findings,  I did not want to hold back from me (sorry, Stephen, for postponing the "HIIT Manual"-post, once again, but think about it like that, what's the use of working out if your MSG intake would quash your results anyway ;-)

• * See figure 2 for exact data on the average daily human intake of MSG - with 91mg MSG /kg body weight, an amount that would translate to a daily intake of ~500+mg MSG in humans, the mice in the Collison were representative of the average American, yet not the Thai, Japanese and Korean MSG intake; against that background it is  important to note that MSG ingestion alone did not result in microscopic fat deposits in the liver. These effects were exclusively observed upon co-ingestion of the MSG with a diet with ~9% TFA content!
  "MSG intake at doses similar to human average daily intake[*] caused hepatic microsteatosis and the expression of beta-oxidative genes." - in a 2009 study, Collison confirmed the negative effects of even moderate MSG intake on liver health in a rodent model; only the common combination of trans-fatty acids (TFA) + MSG that is one of the main characteristics of modern "convenience" foods, did yet induce statistically significant increases in liver weight and hepatic triglyceride content; the increases in total, but also HDL cholesterol due to MSG + TFA were accompanied by profound increases in circulating leptin levels, probably in response to developing leptin resistance and increased storage of lipids in the white adipose tissue stores of the nine-week old C57BL/6J mice (Collison. 2009); in a follow up study Collison et al. confirmed that the double-whammy of trans-fatty acids + MSG becomes even more toxic if a third villain is added to the mixture, high fructose corn syrup (Collison. 2011) - and I don't have to tell you where in the human food chain you will find this unholy trinity, do I?
• "MSG ingestion reduces weight gain, body fat mass, and plasma leptin levels" - in a 2008 trial Kondoh and Torii observed a very different and in fact surprisingly pronounced beneficial effect of the ingestion of a 1% solution (in biology this means 1g per 100ml) MSG resulted in decreases in weight gain, body fat mass and plasma leptin levels in male Sprague-Dawley rats irrespective of the energy content of their diets (!) and without effecting total energy intake or food intake, but in the presence of a profound decrease in 24h-water intake (2g vs. 9g); these effects were observed in both adult and young animals, in the latter without any negative side effects on the normal development of body length

  

  Figure 1: Leptin levels (ng/ml) on diets with different energy density and macronturient composition with or without MSG added to the water (data based on Kondoh. 2008)

  this leaves more than enough room to speculate about centrally mediated increases in energy expenditure in response to the ~20mg total MSG (equivalent to 33mg/kg for a rodent and a human equivalent dose of ~5.5mg/kg) intake of which Kondoh and Torii speculate that they may be "mediated via gut [glutamate] receptors functionally linked to the afferent branches of the vagus." (Kondoh. 2008); subsequent studies into the effects of MSG on the "gut brain axis" appear to support this hypothesis (cf. Kondoh. 2009a,b; Otsubo. 2011)
• " MSG, in spite of mild hypophagia [reduced food intake], caused severe increase in fat body weight ratio, via leptin resistance" - in 2011 Afifi and Abbas, two researchers from the Department of Biochemistry at the Zagazig University in Egypt, report that feeding high amounts of MSG to pregnant rat dams had similar negative effects on body composition and leptin sensitivity as a hypercaloric diet and that despite an overall reduction in total food intake; moreover, despite similar gains in body fat, the negative effects on the offspring of those pregnant rats was more pronounced than in the rats on the "normal" hypercaloric diet (Afifi. 2011)
• If you suffer from "Chinese Restaurant Syndrome", you should check whether increased gastrointestinal permeability could be the root cause of your problems and avoid all foods with any of the following "ingredients": E620 Glutamic acid, E621 Mono-sodium glutamate, E622 Mono-potassium glutamate, E623 Calcium diglutamate, E624 Mono-ammonium glutamate, E625 Magnesium diglutamate!
  "Findings from the literature indicate that there is no consistent evidence to suggest that individuals may be uniquely sensitive to MSG" - in one of the few reviews evaluating exclusively human studies, Freeman did not find any placebo controlled research that would confirm the universal existence of side-effects (e.g. headaches, chest pain, flushing, numbness or burning in or around the mouth, sense of facial pressure or swelling and sweating) as a direct consequence of the consumption of food-borne mono-sodium glutamate; e.g.
  

  "The present study led to the conclusion that 'Chinese Restaurant Syndrome' is an anecdote applied to a variety of postprandial illnesses; rigorous and realistic scientific evidence linking the syndrome to MSG could not be found." (Tarasov. 1993)

  instead, the author suggests that "unique sensitivities" could explain the documented case reports (Freeman. 2008 // see also Walker. 2000; Geha. 2000); given the emerging evidence of the existence of something you could call a "leaky brain" (in analogy to "leaky gut"), it appears likely that an unnaturally increased permeability of the blood-brain-barrier and subsequent penetration of large amounts of glutamate into the brain even at lower serum concentrations could well explain those differences (although not directly related to MSG, I would still like to point you to the results of a recently released study, which found a profound decrease in the permeability of the BBB in response to an oral 1mg/kg (HED ~0.16mg/kg) Lycium barbarum extract in an experimental stroke model; Yang. 2013)
• "dietary antioxidants have protective potential against oxidative stress induced by MSG" - in 2006 Faromby and Onyema observed that previously described oxidative damage to the liver and subsequent steatosis (lipid accumulation) in response to the intra-peritoneal administration of ridiculously high amounts of MSG (4g/kg body weight) could be ameliorated by vitamin C + vitamin E + quercitin; these results suggest that exorbitantly high doses of MSG (human equivalent ~51g/day) are probably a result of an increase in reactive oxygen species
• "after intragastric administration of MSG, the MSG is preferentially metabolized through gluconeogenesis in B6 mice, whereas thermogenesis is the predominant process for 129 mice" - in previous studies scientists had observed profound differences in terms of the effects of MSG on food intake and preference; in 2009 Bachmanov et al. traced those differences back to genetic polymorphisms and respective differences in the metabolic response to / utilization of MSG - if we assume that similar differences exist in human beings, those would provide another explanation for the different incarnations of the "Chinese Restaurant Syndrome" with the classic headaches, high blood pressure and sweating in people who would be long to the human equivalent of the 129 mice and the highly rewarding and appetite stimulating gluconeogenic (hepatic production of glucose from the glutamate) effects in those humans with a similar genetic programming as the B6 mice

I could certainly go on for hours, citing study after study with "evidence" and "counter-evidence", or rather what the respective authors consider as such, but I believe that you have read enough to see a couple of basic patterns emerge, here.

So what about those differences? Genes, dosages, or what?

One of these patterns is also brought up by Kondoha and Torii in the discussion of the results of their study (remember: decrease in body fat and increase in energy expenditure; purported mechanism = activation of glutamate receptors that are linked to the vagus nerve), in which the researchers state that they believe that the diametrically opposed results of their, compared to other studies (most of which report an increase not a decrease in body fat that is accompanied by increases in circulating leptin and decreases in leptin sensitivity and not vice versa as in the Kondoh study), may well be explained by

[previous] studies [being] designed specifically to produce toxic effects in the brain (where GLU is an excitatory neurotransmitter), through the administration of extremely high doses (2000 mg/kg or more, administered repeatedly) to infant animals, either by single, direct injection or intubation (Kondoh. 2008).

Those high dosages could in fact have lead to blood glutamate concentrations that would allow the flux of the excitatory amino acid even across intact blood-brain-barriers. The more realistic, orally administered dosages  Kondoh and Torii used in their experiment, on the other hand, did not induce any (not even statistically non-significant) elevations of serum glutamate levels.

Hence, the effects seen in the present study, as discussed above, are probably linked via a physiologic mechanism, to a local action of GLU in the gut, rather than via a pharmacologic/toxicologic mechanism to a distant action of exogenous GLU forced on the brain (Kondoh. 2008).

If you review the brief rundown of the literature I've provided in the previous paragraphs you will have to acknowledge the validity of this remark (remember: the steatosis in the Collison study required co-administration of trans-fatty acids /TFA/ and even then the increase solely due to MSG was marginal compared to that of the TFAs, alone).

Without a leaky gut, you would probably have to eat pure MSG all day to do harm

If you also take into account, that in healthy individuals only <5% of the dietary glutamate are actually absorbed into systemic circulation, while the rest is used as an oxidative substrate by the intestinal mucosa (Smriga. 2007), the difference between thhe orally consumed 33mg/kg MSG that helped the rodents in the study by Kondoh and Torii to lean out and the intraperitoneally injected 4,000mg/kg that were necessary to induce the touted hepatic side effects in the study by Faromby and Onyema are way above the average intake even the worst offenders among the MSG abusers are exposed to (cf. figure 2):

Figure 1: Average per capita daily MSG intake in different countries (adapted from Löliger. 2000)

Even if we discard the oxidative loss within the intestine, those 4,000mg/kg for a rodent (in previous studies Onyema et al. had even used 6,000mg/kg to elicit the hepatic damage; Onyema. 2006) would translate to ~650mg/kg in humans and would mean that you would have to shovel down anywhere between 32g and 64g of pure MSG (depending on whether you weigh 50 or 100kg), i.e. 20-40x more than the average daily intake of a Korean (note: The "rodent model of MSG induced obesity" is induced by injection of 10,000mg/kg body weight; cf. Bunyan. 1976) and the whopping MSG equivalent of 400-800ml of soy sauce (avg. MSG content 80mg/ml), which is probably the worst offender in the E-number-laden ingredient arsenal of the Asian cuisine.

Figure 3: Protein-bound and free glutamate content of "high" glutamate foods (left) and total glutamate content of selected plant proteins (right; data adapted from Loliger. 2000)

Your best bet to ingest similar amounts of free glutamate from real foods is, as the data from a review by Loliger suggests (cf. figure 3), would be parmesan cheeese, but in all honesty, in view of the fact that you would have to consume 2.6kg of the Italian delicacy, it is pretty unlikely that the glutamate and not the sheer amount of pure energy in the cheese would be the underlying reason for subsequent weight gain. Against that background it should not be surprising that negative side-effects as they occur as a result of high to unrealistically high MSG intakes and or in especially susceptible individuals, are not exactly common in people who don't eat out and/or consume pre-packaged convenient foods on a regular, if not daily basis.

Too much of a vitally important thing at the wrong time and as part of the wrong foods...

The mere presence of non-negligible amounts of glutamate in all sorts of "real" foods, should yet remind you that glutamate is not a toxin, or a "foreign substance" we are not evolutionary adapted to, but an amino acid that is of utmost importance for the health of your central nervous system (Platt. 2005). So that at the end of this analysis we may not be back at square one, but still have to concede that it brought us back to a set of very common motifs here at the SuppVersity:

• When consumed in excess, substances that are good, healthy, beneficial and even "vitally" (=vitamin ;-) important can easily turn against you
• When substances do not have to pass the gut, the dose-response relationship can differ so substantially that results that are acquired using route A (e.g. intraperitoneal injection) cannot simply be transfered to scenarios employing different administration routes (e.g. oral ingestion)
• Inter-individual/-species differences and differences between healthy and unhealthy individuals / animals, warrant utmost caution, when it comes to interpreting data - the "Chinese Restaurant Syndrome", for example, could be a result of increased gut and blood-brain-barrier permeability that would lead to an increased absorption of glutamate from the intestine into the blood and from there across the blood-brain-barrier right into the brain.
• Oftentimes, differences due to the aforementioned factors are not of simple quantitative, but of qualitative nature, in the case of MSG this would be the difference between the metabolic activation in response to the local activation of glutamate receptors in the gut that are connected to the vagus nerve, on the one hand, and the systemic / central obesogenic (fattening) effects of glutamate that leaks from the gut into the blood and from there into the brain.

And lastly, to eventually come full circle and remind you of the results of Collison et al., we cannot ignore that MSG is one of those substances that is usually found in foods with a whole host of other nutrient-poor ingredients, anti-nutrients and proven obesogenic, pro-inflammatory and otherwise unhealthy substances and food additives. They are wrapped in plastics have an extended shelf life due to tons of preservatives and highly adorned with stickers and labels saying "low this", "extra that", "only X amounts of calories", etc. - as long as you avoid those foods on 360+ days of the year, prepare your meals from whole foods, don't dine at cheap restaurants, fast-food outlets and snack bars too often or try to find the "optimal amount of supplemental MSG to stimulate your vagus nerve and help you shed fat" *lol*, you can calmly watch the ever-recurring MSG scares on the Internet and other mass media ;-)

References:

1. Afifi MM, Abbas AM. Monosodium glutamate versus diet induced obesity in pregnant rats and their offspring. Acta Physiol Hung. 2011 Jun;98(2):177-88.
2. Bachmanov AA, Inoue M, Ji H, Murata Y, Tordoff MG, Beauchamp GK. Glutamate taste and appetite in laboratory mice: physiologic and genetic analyses. Am J Clin Nutr. 2009 Sep;90(3):756S-763S. Epub 2009 Jul 1.
3. Bachmanov AA, Inoue M, Ji H, Murata Y, Tordoff MG, Beauchamp GK. Glutamate taste and appetite in laboratory mice: physiologic and genetic analyses. Am J Clin Nutr. 2009 Sep;90(3):756S-763S. Epub 2009 Jul 1.  
4. Bunyan J, Murrell EA, Shah PP. The induction of obesity in rodents by means of monosodium glutamate. Br J Nutr. 1976 Jan;35(1):25-39.
5. Collison KS, Maqbool Z, Saleh SM, Inglis A, Makhoul NJ, Bakheet R, Al-Johi M, Al-Rabiah R, Zaidi MZ, Al-Mohanna FA. Effect of dietary monosodium glutamate on trans fat-induced nonalcoholic fatty liver disease. J Lipid Res. 2009 Aug;50(8):1521-37. Epub 2008 Nov 11.  
6. Collison KS, Zaidi MZ, Saleh SM, Makhoul NJ, Inglis A, Burrows J, Araujo JA, Al-Mohanna FA. Nutrigenomics of hepatic steatosis in a feline model: effect of monosodium glutamate, fructose, and Trans-fat feeding. Genes Nutr. 2013 Apr;7(2):265-80. Epub 2011 Dec 6. 
7. Farombi EO, Onyema OO. Monosodium glutamate-induced oxidative damage and genotoxicity in the rat: modulatory role of vitamin C, vitamin E and quercetin. Hum Exp Toxicol. 2006 May;25(5):251-9.
8. Freeman M. Reconsidering the effects of monosodium glutamate: a literature review. J Am Acad Nurse Pract. 2006 Oct;18(10):482-6.nonalcoholic fatty liver disease. J Lipid Res. 2009 Aug;50(8):1521-37. Epub 2008 Nov 11.
9. Geha RS, Beiser A, Ren C, Patterson R, Greenberger PA, Grammer LC, Ditto AM, Harris KE, Shaughnessy MA, Yarnold PR, Corren J, Saxon A. Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study. J Nutr. 2000 Apr;130(4S Suppl):1058S-62S.
10. Hermanussen M, García AP, Sunder M, Voigt M, Salazar V, Tresguerres JA. Obesity, voracity, and short stature: the impact of glutamate on the regulation of appetite. Eur J Clin Nutr. 2006 Jan;60(1):25-31. 
11. Insawang T, Selmi C, CHa'on U et al. Monosodium glutamate (MSG) intake is associated with the prevalence of metabolic syndrome in a rural Thai population. Nutrition & Metabolism 2013, 9:50 doi:10.1186/1743-7075-9-50
12. Iwase M, Ichikawa K, Tashiro K, Iino K, Shinohara N, Ibayashi S, Yoshinari M, Fujishima M. Effects of monosodium glutamate-induced obesity in spontaneously hypertensive rats vs. Wistar Kyoto rats: serum leptin and blood flow to brown adipose tissue. Hypertens Res. 2000 Sep;23(5):503-10.
13. Kondoh T, Torii K. MSG intake suppresses weight gain, fat deposition, and plasma leptin levels in male Sprague-Dawley rats. Physiol Behav. 2008 Sep 3;95(1-2):135-44. 
14. Kondoh T, Tsurugizawa T, Torii K. Brain functional changes in rats administered with monosodium L-glutamate in the stomach. Ann N Y Acad Sci. 2009a Jul;1170:77-81.
15. Kondoh T, Mallick HN, Torii K. Activation of the gut-brain axis by dietary glutamate and physiologic significance in energy homeostasis. Am J Clin Nutr. 2009b Sep;90(3):832S-837S.
16. Loliger J. Function and importance of glutamate for savory foods. J Nutr. 2000 Apr;130(4S Suppl):915S-20S. 
17. Otsubo H, Kondoh T, Shibata M, Torii K, Ueta Y. Induction of Fos expression in the rat forebrain after intragastric administration of monosodium L-glutamate, glucose and NaCl. Neuroscience. 2011 Nov 24;196:97-103.
18. Onyema OO, Farombi EO, Emerole GO, Ukoha AI, Onyeze GO. Effect of vitamin E on monosodium glutamate induced hepatotoxicity and oxidative stress in rats. Indian J Biochem Biophys. 2006 Feb;43(1):20-4.
19. Pavlovic V, Sarac M. The role of ascorbic acid and monosodium glutamate in thymocyte apoptosis. Bratisl Lek Listy. 2010;111(6):357-60. 
20. Platt SR. The role of glutamate in central nervous system health and disease--a review. Vet J. 2007 Mar;173(2):278-86.
21. Ren X, Ferreira JG, Yeckel CW, Kondoh T, de Araujo IE. Effects of ad libitum ingestion of monosodium glutamate on weight gain in C57BL6/J mice. Digestion. 2011;83 Suppl 1:32-6. Epub 2011 Mar 10. 
22. Smriga M. COFAG comments on: "Monosodium glutamate-induced oxidative damage and genotoxicity in the rat: modulatory role of vitamin C, vitamin E and quercetin". Hum Exp Toxicol. 2007 Oct;26(10):833-4; author reply 835-6. 
23. Tarasoff L, Kelly MF. Monosodium L-glutamate: a double-blind study and review.
    Food Chem Toxicol. 1993 Dec;31(12):1019-35.
24. Walker R, Lupien JR. The safety evaluation of monosodium glutamate. J Nutr. 2000 Apr;130(4S Suppl):1049S-52S.
25. Yang D, Li SY, Yeung CM, Chang RC, So KF, Wong D, Lo AC. Lycium barbarum extracts protect the brain from blood-brain barrier disruption and cerebral edema in experimental stroke. PLoS One. 2013;7(3):e33596. Epub 2013 Mar 16.

Want to Cut 12% Body Fat in 12 Weeks, Get Stronger, Bigger or Better Conditioned? Periodize Appropriately!

Image 1 (hitchfit.com): I know I am repeating myself, here, but 12% less body fat mass in 12 weeks without dieting should be a reason to pick up those dumbbells, ladies, right?

If you have read Adelfo's blogpost, yesterday, you will have noticed the versatility of his routine. The combination of volume, 5x5 and EDT training, which may appear somewhat chaotic at first, is yet well-planned, clearly structured and has little of the "cookie-cutter" approach to training people follow who will tell you in the locker room, whenever you meet them: "Ah, I better train biceps today, my legs don't feel right, bro" ;-) In the end, Adelfo's approach is just an unconventional twist on undulating periodization; in other words, a training split where you switch your rep and set numbers in relatively short (but regular!) intervals - often from one training to the next. But is this really the optimal way to train? I mean HST = hypertrophy specific training looks different and that is "hypertrophy specific", right? And in fact, if analyzed on its own, a recently published study from Brazil appears to suggest that what Adelfo feels is the best way to train could in fact be inferior to a less sophisticated linear periodization program  (de Lima. 2013). - and you know what? At least for his sedentary cousin that may in fact be right!

Lifting weights works! Regardless of how you periodize, but...

The 28 healthy, normal-weight, formerly sedentary women (age 20–35; body fat ~25%) from the de Lima study had been randomly assigned to follow 2-day body split routines which differed only with respect to the means of periodization, i.e. the sequence of lower vs. higher rep work (see illustration 1 for an outline of the training regimen) for 12 weeks (no dietary changes or other inventions).

Illustration 1: Outline of the workout (left) and periodization regimen (right) the 28 young women followed over the course of the 12-week intervention period (de Lima. 2013)

If we based our predictions on previous data in 28 recreationally trained college-aged men (Buford. 2007), 40 young men (21.5y) with a minimum 1-year strength training experience (Prestes. 2009a) and 20 resistance trained men (26y; 4-5 years of training experience; Miranda.. 2007) both conducted with linear vs. undulating periodization schemes in the strength-to-hypertrophy rep ranges of 4-8 and 4-14 reps, respectively, we would expect either no difference (Buford. 2007) or a slight advantage for the undulating periodization protocol with respect to its effects on maximal strength (Prestes. 2009 a,b).

Figure 1: Rel. changes in body composition, maximal strength and strength endurance (de Lima 2013)

As the data in figure 1 shows, neither of those predictions is accurate. Contrary to Buford et al. de Lima et al. did observe statistically significant differences between the study arms, yet other than Prestes et al. those changes were not in the maximal strength, but rather in the strength endurance domain. And while the latter showed significantly greater improvement in the women who trained according to the undulating periodization protocol, the classic, some people would probably say "boring", linear periodization protocol elicited a substantially more pronounced decreases in body fat and increases in strength.

Periodicize according to your training level & goals

As boring as those highly structured linear periodization protocols may be, the results from the de Lima study would suggest that there is a reason why Brian Haycock's HST (=Hypertrophy Specific Training) periodization prescriptions are downright anal. It is also reasonable to assume that for beginners and (early) advanced trainees, long(er) cycles will allow for optimal structural adaptations to the individual loading patterns, with the "growths" phases in the medium (8-12) rep ranges and facilitative strength gains and endurance gains in the lower-rep (4-6) respectively higher rep (15-20) weeks. It is also interesting to note that in these early days, when trainees makes the transition from undermuscled couch potato to "recreationally active" muscle gains and fat loss are coupled and can, as the data from the de Lima study shows, be influenced not just by modulating the total number of sets (volume) or the rep range, but also by changing the sequence of phases of training at the upper, medium and lower range of a given set x rep continuum (here 3x15-3x30) - that the latter was somewhat higher than normal (here "normal" indicates 6-15), may have exerted confounding effects, but it does not take away from the constantly overlooked, yet non-negligible effects different means of periodization exert on both your performance and your body composition!

Chest	Biceps	Back	Core	Legs	Triceps	Shoulders
Navigate the SuppVersity EMG Series and learn about the best exercises for a given body part (incl. example workouts).

The studies by Buford Miranda and Prestes on the other hand, suggest that those facilitative strength and strength endurance gains, without which no strength trainee, rookie, advanced or veteran will be able to generate the necessary overload to cause structural adaptations, or put simply, skeletal muscle hypertrophy, may require a slightly more creative, yet by no means chaotic workout organization, once you have a couple of years of weight lifting under your belt.

Daily vs. weekly undulation? I am with Dr. Hatfield and prefer the former!

Personally I prefer the intra-workout or as Miranda et al. call it "daily undulatory" periodization à la Dr. Squat (Hatfield): It makes training more fun and allows me to perform every exercise and train for every body part in a rep range of which I feel that it suits it best:

• lower rep work and a focus on continuously increasing the poundage on compound exercises, such as the squat, deadlift, bench press, military press, pull ups and bend over rows at the beginning of my workouts or as the first exercise for a given body part
• medium and sometimes high(er) rep work and a focus on maximal muscle tension on auxiliary exercises such as biceps curls, triceps extensions, flys, cable cross, pullovers, seated rows, dumbbell rows, reverse DB/cable flys, side laterals, upright rows and shrugs in the latter part of my workouts or as follow up exercises for a given body part

And though Miranda et al. may not have found statistically significant differences in any of the individual tests the 20 strength training veterans in their study had to perform, the greater effect sizes in the undulating periodization group (1.54 = large for daily undulating periodization vs. 1.04  = moderate for linear periodization) appear to prove my instincts and training experience right ... but to be honest, even if it didn't I would rather train "suboptimal" than bore myself to death during another HST (=linear periodization) cycle.

Ressources:

1. Buford TW, Rossi SJ, Smith DB, Warren AJ. A comparison of periodization models  during nine weeks with equated volume and intensity for strength. J Strength Cond Res. 2007 Nov;21(4):1245-50. 
2. de Lima C, Boullosa DA, Frollini AB, Donatto FF, Leite RD, Gonelli PR, Montebello MI, Prestes J, Cesar MC. Linear and Daily Undulating Resistance Training Periodizations Have Differential Beneficial Effects in Young Sedentary Women. Int J Sports Med. 2013 May 4
3. Miranda F, Simão R, Rhea M, Bunker D, Prestes J, Leite RD, Miranda H, de Salles BF, Novaes J. Effects of linear vs. daily undulatory periodized resistance training on maximal and submaximal strength gains. J Strength Cond Res. 2011 Jul;25(7):1824-30.
4. Prestes J, Frollini AB, de Lima C, Donatto FF, Foschini D, de Cássia Marqueti R, Figueira A Jr, Fleck SJ. Comparison between linear and daily undulating periodized resistance training to increase strength. J Strength Cond Res. 2009 Dec;23(9):2437-42.
5. Prestes J, De Lima C, Frollini AB, Donatto FF, Conte M. Comparison of linear and reverse linear periodization effects on maximal strength and body composition. J Strength Cond Res. 2009 Jan;23(1):266-74.