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Sabtu, 05 Maret 2016

Recent Studies Cast Shadow Over High Dose BCAA Intake: Increased Protein Wasting, Lower Brain Serotonin and More

To guzzle BCAAs all day or not - is that still a question or is the answer settled with the publication of two recent studies?
From previous SuppVersity articles about BCAA you will know that I don't buy into the hype supplement producers generate about the muscle-building and/or muscle-protective effects of high dose BCAA- or leucine-only supplementation.

One of the previously mentioned issues with BCAAs are their putative ill effects on neurotransmitter levels in the brain - effects that had only been observed in rodents, though. Now, a recent study in pigs, who are a much better model of human metabolism (even much better than most apes | Miller. 1987), is fueling the concerns about the pro-depression effects of high dose leucine supplementation.
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The corresponding study  (Wessels. 2016), which happens to have been sponsored by the BCAA producer Ajinomoto (quite ironic, isn't it?), sought to elucidate the response of high leucine diets on the activity of the BCAA metabolizing enzyme branched-chain keto acid dehydrogenase complex (BCKDH) and subsequent changes in the concentrations of free amino acids and amino acid derivates in several tissues, including the brain.

Figure 1: Brian tryptophan and serotonin levels in response to diets containing normal or two- (white) and four-fold (grey bar) elevated amounts of leucine (Wessels. 2016).
What the scientists found was a significant decrease in brain tryptophan with twice and a significant reduction of both brain tryptohan and serotonin levels with four times the regular amount of leucine in the piglets' diets (that's 1% vs. 2% vs. 4%). Bad news!? Well, 4% leucine in the diet are a very high amount with questionable practical implications. Even though the study confirms the potentially negative effects of the tryptophan blocking effects of leucine and BCAAs in general, the good think is that it assigns a relatively high number to the required dosage to see effects - whether lower doses would suffice to mess with all three BCAAs, as they were used by Choi et al. (2013), remains elusive, though.
In vivo comparison of the central action of isoleucine, valine, and leucine on glucose kinetics during pancreatic insulin clamps (Arrieta-Cruz. 2016).
It's not all bad news: While the potentially depression promoting effects of high dose leucine and the anti-anabolic / pro-catabolic effects of BCAA supplementa-tion in rodents are bad news, another recent study from the Mexican Ministry of Health supports the previously discussed anti-diabetic effects of isoleucine and sug-gests that valine may have similar effects. In view of the fact that the putative mechanism, for the increased glucose infusion rate (GIR | see Figure on the left) is an increased inhibitory effect of insulin on endogenous glucose production (EGP), not an increase in peripheral glucose utilization, it is yet questionable how relevant the results of Arrieta-Cruz' recent study in diet-induced o-bese rats are for athletes / healthy individuals for whom exuberant glycolysis / gluconeogenesis isn't a problem.
While it obviously depends on the severity of your BCAA addiction, whether the Wessels study is bad news for you, it is it is unfortunately too early to rejoice: More potentially bad news for BCAA junkies comes from a recent study by Milan Holecek et al. (2016) whose efforts to prove that diets containing extra BCAAs (valine, leucine, and isoleucine | HVLID), or a high(er) content of leucine (HLD) would have beneficial effects on the protein balance of rats in a two months study produced results neither the scientists nor I would have expected: In high doses BCAAs make your body waste protein!
Figure 2: BCAA content of the standard (SLD), high BCAA (HVLID) and high leucine (HLD) diets (Holecek. 2016).
Needless to say that this result is in diametrical contrast to what the scientists expected. Not only did Holecek et al. fail to demonstrate the expected positive effects of the chronic consumption of a BCAA- / leucine-enriched diet on protein balance in skeletal muscle. The results of their latest study actually "indicate rather negative effects from a leucine-enriched diet" (Holecek. 2015).
But BCAAs are muscle-builders how can leucine & co ruin protein synthesis? A reliable answer to this question has unfortunately yet not been found, but the results of the Holecek study suggest that an overabundance of BCAAs triggers an overexpression of the BCAA degrading enzyme BCKA dehydrogenase and the subsequent conversion of BCAAs to BCAA keto acids and / or eventually alanine or glutamine which are then (ab-)used as energy source by the liver (cf. modified figure from Holeček. 2001)
Instead of reducing the breakdown of protein, Holecek et al. found that a BCAA- or leucine-enriched diet tends to increase not just the breakdown of BCAAs, as well as the production of branch-chain keto acids (BCKA), alanine and glutamine and their utilization in visceral organs, it also impaired the rodent's protein synthetic response to a meal in postabsorptive state - particularly in fast-twitch (white) muscles.
Figure 3: Fractional rate of protein synthesis. Means ± SE, p < 0.05. *compared to the corresponding control (SLD or SLD + S); # compared to the corresponding fed group; † HLD (HLD + S) group vs. HVLID (HVLID + S) group (Holecek. 2016).
In spite of the fact that this increase in protein wastefulness, as I would call it, is bad news and the exact opposite of what the shiny BCAA ads and product write-ups promise, a significant loss in muscle weight was only observed in the soleus and ext. digitorum longus of the rodents in the high BCAA, but not the high leucine group. Accordingly, the study sheds a whole new light on the usefulness of BCAAs as 'muscle builders' or 'muscle protectors' and may, as Holecek et al. rightly point out...
"[...] explain the discrepancy between the protein anabolic effects of BCAA or leucine on muscles that were reported under in vitro conditions and/or shortly after BCAA intake and their reduced or lack of effects following chronic administration" (Holecek. 2016).
With the present study being conducted in healthy rodents without any of the condition that lead to muscle wasting (e.g. disorders like diabetes, or natural processes like aging) and in the absence of the stimulatory effect of exercise on signalling pathways that activate protein synthesis, future studies will have to determine, whether the ill effects on protein synthesis and increases in protein breakdown are (a) even more severe in muscle-wasting disorders, the elderly, and / or during endurance exercise, and how (b) the effects are modified by resistance training.
Figure 4: The previously not discussed ill (BCAA) and beneficial (leucine) effects of different levels of said amino acids on the HDL to LDL ratio of the rodents in the Holecek study should be taken into account, as well.
Bottom line: While the main outcomes of the two studies I discussed in detail in today's SuppVersity article do in fact cast a dark shadow on the health and performance benefits of BCAAs, it's not all bad news. Why's that? Here's why: (A) the Wessels study suggests that the amount of BCAAs that is required to produce practically significant reductions in brain serotonin is very high; (B) the significant reduction in the LDL/HDL ratio Holecek observed in the high leucine group of their study (Figure 4) and the lack of visible effects on actual muscle mass in the same group put the relevance of the increased protein breakdown in response to (at least) high dose leucine into perspective; and (C) there's still the Arrieta-Cruz study which shows that even isoleucine and valine of which the Holecek study draws a rather negative image, can have benefits - at least in the obese | Comment!
References:
  • Arrieta-Cruz, Isabel, Ya Su, and Roger Gutiérrez-Juárez. "Suppression of Endogenous Glucose Production by Isoleucine and Valine and Impact of Diet Composition." Nutrients 8.2 (2016): 79.
  • Choi S, Disilvio B, Fernstrom MH, Fernstrom JD. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines. Amino Acids. 2013 Aug 1. [Epub ahead of print] 
  • FAO (Food and Agriculture Organization of the United Nations. "Food and nutrition in numbers." Rome, 2014; Food and Agriculture Organization of the United Nations.
  • Holeček, Milan. "The BCAA–BCKA cycle: its relation to alanine and glutamine synthesis and protein balance." Nutrition 17.1 (2001): 70.
  • Holeček, Milan, et al. "Alterations in protein and amino acid metabolism in rats fed a branched-chain amino acid-or leucine-enriched diet during postprandial and postabsorptive states." Nutrition & metabolism 13.1 (2016): 1.
  • Miller, E. R., and D. E. Ullrey. "The pig as a model for human nutrition." Annual review of nutrition 7.1 (1987): 361-382.
  • Wessels, et al. "Branched-Chain Amino Acid Degradation and Modify Serotonin and Ketone Body Concentrations in a Pig Model." PLoS ONE 11.3 (2016).

Jumat, 19 Februari 2016

High Dose Stevia Turns Weight Gain into Loss, Lowers Lipid and Glucose Levels not Only When Used to Replace Sugar - Effects are Mediated by Reduced Energy Intake & Utilization

There's very little "natural" about the natural sweetener stevia when it ends up in your food in form of purified and decolorized steviosids.
As a SuppVersity reader you'll know that "natural" does not equate "healthy". This, the proven anti-microbial effects stevia exerts in your gut and the fact that the currently available steviosid-based stevia products undergo more processing steps than than the dreaded aspartame warrant the question whether (a) stevia is safe and (b) as effective as other sweeteners when it comes to weight loss promotion.

Since the optimal dosage of stevia to achieve meaningful effects is also not known, yet, scientists from the Alexandria University in Egypt investigated the safety ad efficacy of different amounts of stevia sweeteners (25, 250, 500 and 1000 mg/kg body weight per day) as a substitute for sucrose on weight gain or the weight loss and weight management of female rats on an ad-libitum diet.
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Sixty adult female Wistar strain rats (average weight 203 ± 6 g) were used in the present experiment. Animals were obtained from Faculty of Medicine, Alexandria University, Egypt. Animals were caged in groups of 6 and given distilled water and a standard diet that meets their requirements for growing ad libitum. The diet consisted of  44% soybean cake; 12% berseem clover hay, 13.5% fat, 9.8% yellow maize, 13.2% starch, 5% minerals; 2% lime stone and 0.5% vitamins mixture. After two weks of acclimatization, animals were divided into six equal groups:
  • The first group was drank distilled water (Negative control), and positive control was given a dose of sucrose dissolved in drinking water at 500 mg/kg/day. This dose of sucrose used in this experiment was predicted to dose of stevia sweeteners equivalent concentration estimated by JECFA as control. 
  • "On the other hand, groups 3, 4, 5 and 6 were given a different doses of stevia sweeteners which were dissolved in drinking water at a dose level of 25 mg/kg/day (human equivalent dosage, HED = 4 mg/kg/day) according to JECFA (G1), 250 mg/kg/day (G2: HED = 41 mg//kg/day), 500 mg/kg/day (G3: HED = 81 mg/kg/day) and 1000 mg/kg/day (G4: HED = 162 mg/kg/day ), respectively" (Elnaga. 2016)
To assess how much stevia the animals actually consumed, the scientists recorded the animals fluid intake daily. To ensure constant intakes in all groups, they adjusted the solution concentrations weekly based on the average weight of the animals and their current fluid consumption.
At the end of the experimental period (12 weeks), body weights of animals were recorded and calculated of body weights gain (%) and feed efficiency ratio (FER) according to the method of Chapman et al. (1959).
Figure 1: Body weight of rats treated with administration of sucrose (S) and stevia sweetener different dosages (25, 250, 500 and 1000 mg/kg) for 12 weeks compared with control (Elnaga. 2016).
You probably expected that the replacement of sugar with stevia would lead to significant reductions in body weight gain, right? Well, if you scrutinize the data in Figure 1, you will notice that the effect went far beyond a reduction in weight gain. In fact, all stevia supplemented animals lost weight - dose-dependently 40.29%-48.29%.
Figure 2: Organ weights relative to body weight of female rats treated with stevia sweetener at doses of 25, 250, 500 and 1000 mg/kg b. wt and sucrose compared with control (Elnaga. 2016).
This certainly sounds like bad news, but the data in Figure 2 tells you that the weight of all important organs (liver, heart, brain, kidney, lung, pancreas and spleen) remained stable. Unfortunately, the scientists did not measure muscle and fatpad weight.
Figure 3: Final body weight, feed intake and body weight gain % in rats treated with administration of stevia sweetener in different dosages (25, 250, 500 and 1000 mg/kg) after 12 weeks on ad-libitum diet (Elnaga. 2016).
In view of the significantly reduced feed intake (>50%) and the even more reduced feed efficiency ratio (FER), of which the scientists say that it was the lowest at a dose 1000 mg/kg b.wt stevia ( -6.14) and increased with decreasing stevia intakes (-5.21, -3.22 FER and -2.91 FER), it would yet be unreasonable to assume that the weight difference was a results of fat loss, alone.
What about human studies? And what's the mechanism? Comparable human studies haven't been done and the fact that a 2005 study by Chang et al. suggests that the body weight loss of rats receiving 5.0 mg/kg stevioside was due to the poor palatability of the food because of the high amount of stevioside. It is thus questionable if stevia would work the same magic in humans. Ok, in the study at hand, the sweetener was gavaged in the drinking water, but the food intake still decreased significantly. Significantly enough to trigger profound weight loss even in the absence of the reduced feed efficacy (see Figure 3); and even the reductions in blood lipids and glucose could eventually be a function of weight loss - even though, studies appear to suggest that stevia has insulinotropic, glucagonostatic, antihyperglycemic, and blood-pressure-lowering effects all of which would suggest that it could be more than a sugar replacement (Gregersen. 2004; Hony. 2006).
Aside from the questionable weight loss, the three groups of rats treated with stevia sweetener showed improvement in lipid profile levels comparing with negative or positive control group. More specifically,
  • ... the total lipid levels of the rodents decreased by 11.96%, 19.89%, 25.03% and 37.07% when rats were given stevia sweetener at doses of 25, 250, 500 and 1000 mg/kg/b. wt, respectively compared to negative control,
  • ... the LDL values in rat serum lipids decreased with increasing the doses of stevia sweetener; rats given stevia sweetener at dose 1000 mg/kg b. wt showed the highest decrease in the LDL (26.50%) followed by those given dose 500 mg/kg (24.36%), dose 250 mg/kg (19.90%) and finally dose 25 mg/kg (15.01%), and 
  • ... the VLDL levels were decreased 3.13%, 11.18%, 19.87% and 26.08% in rats given stevia sweetener at doses of 25, 250, 500 and 1000 mg/kg.
The decreases in total, LDL and VLDL cholesterol stand in contrast to significant increase in HDL and corresponding decreases of the LDL/HDL ratio from 3.43 and 3.76 in the negative and positive control group to 2.90, 2.49, 2.30 and 2.18 in the 25mg/kg, 250mg/kg, 500mg/kg and 1000mg/kg groups, respectively.
Figure 4: Blood lipids and glucose levels after 12 weeks on high sucrose water with different amounts of stevia replacing the sucrose in the water; data expressed relative to negative (=water) control (Elnaga. 2016).
Ill effects on markers of liver health or general blood parameters were not observed and the significant decrease in blood glucose levels, I added to the relative changes in lipid levels in Figure 4, is certainly nothing to be concerned about.
Bottom line: Just as the scientists put it, "the stevia sweetener treated groups showed significantly improvement and ameliorated reduction in bodyweight, BWG % and lesser intake of feed" (Elnaga. 2016). In conjunction with the "decreasing [...] levels of blood glucose, total lipids, total cholesterol, triglycerides and low-density lipoprotein concentrations, and increasing [...] high-density lipoprotein" (ibid.) concentrations the study at hand appears to suggest that stevia was a wonder-drug.

Study indicates stevia kills healthy gut bacteria. So, how bad is it? Are the effects significant, will they have an impact on your overall health and does this mean you must not use stevia any longer? Learn more in this SV Classic
Two things you must not forget, though, are that (a) the health benefits were most pronounced in comparison to the "positive control", i.e. the sucrose guzzling rats that represent the average sugar-sweetened beverage junkie and that (b) the >40% of weight the rodents lost certainly didn't come from body fat, exclusively.

In view of the contemporary lack of data that would confirm the beneficial effects of several grams of stevia (the dose equivalents for an adult are  ~0.2, ~1.6, ~3.2, ~6.5g per day, respectively) on the body composition and lipid levels of human beings, I must caution against being too euphoric about the results of this study, anyways. | Comment!
References:
  • Chang, J. C., et al. "Increase of insulin sensitivity by stevioside in fructose-rich chow-fed rats." Hormone and metabolic research= Hormon-und Stoffwechselforschung= Hormones et metabolisme 37.10 (2005): 610-616.
  • Elnaga, NIE Abo, et al. "Effect of stevia sweetener consumption as non-caloric sweetening on body weight gain and biochemical’s parameters in overweight female rats." Annals of Agricultural Sciences (2016).
  • Gregersen, Søren, et al. "Antihyperglycemic effects of stevioside in type 2 diabetic subjects." Metabolism 53.1 (2004): 73-76.
  • Hong, Jing, et al. "Stevioside counteracts the α-cell hypersecretion caused by long-term palmitate exposure." American Journal of Physiology-Endocrinology and Metabolism 290.3 (2006): E416-E422.