The Overfeeding Overview: High Fat, Carb, Protein, MCTs, Leptin, Testosterone, T3 & Reverse T3 - Get an Overview of the Consequences of Short- & Long-Term Overfeeding

High fat + high carbohydrate foods like mini doughnuts are exactly what you should not eat on a refeed day, let alone during weeks of bulking.

Do you want to know what happens during days and weeks of gluttony? How the effects "bulking" will have on your body weight and composition, depending on where those extra calories come from? Have you wondered what the optimal nutrient composition on refeed days may look like. And are you concerned about the potential the health consequences of bulking?

Yes? In this case, I would suggest you take a closer look at the following overview of the research. An overview that is probably not complete, but it should suffice to provide preliminary answers to the aforementioned questions.

Learn more about the effects of your diet on your health at the SuppVersity

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Carbohydrate Shortage in Paleo Land

• The amount of weight you gain depends on your genes: They are not the only determinant. That's for sure. A 1990 study by Bouchard et al. still leaves no doubt that your genes are one of the most important determinants of the quantity of weight you gain.
  
  In said study the researchers from the Laval University fed 24 sedentary young male twins 1,000kcal extra for six out of seven days of the week. In that the study is not the first to investigate the effects of overfeeding on weight gain in twins. It is yet the first and only one that did this over a period of 100 days and thus with a total energy excess of 84,000 kcal on a diet that contained 50 percent carbohydrate, 35 percent fat, and 15 percent protein.
  

  

  Figure 1: Comparison of the weight (left) and visceral fat (right) gains in twin pairs; high correlations were observed for both, but the correlation was significantly more pronounced for the unhealthy visceral fat than it was for the mere body weight (Bouchard. 1990).

  The data in Figure 1 does probably not need any extra explanations. In view of the fact that similar results have also been observed in previous studies like Poehlman et al. (1986), it should be obvious that the difference between the weight (left) and visceral fat (right) two identical twins gained was significantly smaller the difference between one twin from pair A and one twin from pair B. The statistical analysis of body fat and waist circumference data revealed similar correlations which were most significant for the visceral fat mass and the waist hip sizes, i.e. those quantities that predict the ill health effects of weight gain best.
  
  According to Ukkola, et al. (2001), the genetic differences may partly be mediated by differences in the genetic make-up of ones beta-2 adrenoreceptors with specific variants being associated with greater increases in insulin resistance, body weight and subcutaneous fatness. Other candidates are the cholesterol ester transfer protein (CETP) gene which appears to affect adiposity in response to long-term overfeeding (Terán-García. 2008). Other scientists use similar genetic polymorphisms to explain a general resistance to weight gain during overfeeding via genetically determined variations in nonexercise activity thermogenesis (Vanltallie. 2001).
• Overfeeding fat, carbohydrate or protein, does it make a difference? Studies that compare isocaloric overfeeding are quasi non-existent. What we do have are studies like the one by Horton et al. (1995) that compared high fat vs. high carbohydrate diets (see Figure 2 for macronutrient composition), where the additional energy came from fat or carbohydrates.
  
  In the Horton study this was a 50% extra that was added in form of fat or carbohydrates on top of the baseline diets of the normal-weight and obese subjects. A 50% extra that lead to significant weight gain.
  

  

  Figure 3: Weight gain (left) and increase in energy expenditure (right) in obese and lean subjects in response to carbohydrate and fat overfeeding (Horton. 1995).

  As you can see in Figure 3, both diets led to a rapid increase in body weight, but the trajectory was different. The main and maybe practically relevant difference, though, was that the rapid increase in water and glycogen in the high carbohydrate group was less resilient weight loss in the post-overfeeding period.

No! Carbs are not necessarily more fattening in the obese. It's a commonly held prejudice that carbohydrates are more readily coverted to fat and stored in the obese, but a study by Minehira et al. that investigated just this found that there was not just no difference in de novo lipogenesis with carbohydrate overfeeding between lean and obese individuals, there was also no increase in de novo lipogenesis, at all, when the when the obese subjects were overfed with a high carbohydrate diet for one day (Minehira. 2004).

• 

  Figure 4: Proportion of the energy that was stored as body fat (Horton. 1995).

  If we take a look at the proportion of energy that was stored as body fat in Figure 4, it is obvious why the fat gains lasted longer than the carbohydrate gains. Why? Well, simply because the 14-day overfeeding on fat lead to a significantly higher relative increase in body fat.
  
  Last but not least, it may also be worth mentioning that the the fat gain in the obese group was 89% and 57% higher in the carbohydrate and fat overfeeding group, respectively. An intriguing result that appears to stand in line with dieting studies, where high fat diets are superior to high carbohydrate diets in the obese, but not in lean individuals.
  
  What was not different for obese and lean individuals, though, was the the fact that the carbohydrate overfeeding lead to higher gains in lean mass than the fat overfeeding. A result that should remind you of a previously reported study here at the SuppVersity, in which a no fat bulk lead to significantly greater muscle and significantly lower fat gains than a low fat bulk (see "If You Go "High Carb", You Better Go Really High!" | more). Overall, "bulking", i.e. eating more than you need on any mixed diet, has repeatedly been shown to produce significant increases plasma Somatomedin-C/Insulin-like Growth Factor (SM-C/IGF-l) and testosterone concentrations as well as insulin, of which Forbes et al. speculate that they promote the lean mass increases that are particularly pronounced when overfeeding is combined with resistance training.
  
  In a more nutrient-type specific study b by Dirlewanger that did not focus on the weight gain or anabolism, but on the leptin response and the increase in resting energy expenditure the subjects experienced a significant increase in leptin (+28%) and resting energy only in the high carbohydrate, yet not in the fat overfeeding arm of their study in young, lean individuals (Dirlewanger. 2000). Other studies, without clear distinction between high carb and high fat overfeeding, indicate that fast food like burgers or fries is an effective short-term leptin stimulator, too - at least if it's consumed in a single binge (Kolaczynski,. 1996).
  

  

  Figure 5: Energy partitioning in young men upon overfeeding with ~5,000kcal per day - mostly carbohydrates, i.e. 1% protein, 3% fat, and 86% carbohydrate (Acheson. 1988).

  In the short run, like on refeed days, for example, carbohydrate overfeeding has another advantage over fat overfeeding, because it takes roughly 500g of carbohydrates (that's 2,000kcal) before even a single gram of those carbs is converted to fat and potentially, but not necessarily stored as body fat (Acheson. 1988) - at "only" 400kcal extra from carbs for one day there was no net lipogenesis at all (see Figure 5). This result is corroborated by data from McDevitt et al. (2000) who observed that the fat gain with fat overfeeding starts with day 1, while there is a time gap in the increase in body fat with carbohydrate overfeeding (McDevitt. 2000).

If you consume sugar on a refeed, should you prefer glucose, sucrose of fructose? In view of the fact that I don't suggest you refeed more than 1-2 days and considering the fact that you want to get the majority of your carbs from starches on a true bulks, it does not really matter. In fact, studies show no difference in de novo lipogenesis in 96h overfeeding studies between pure glucose and sucrose, which is a 1:1 combination of fructose or fructose in two studies in lean and obese women by (McDevitt. 2000 & 2001). In the long run, consuming amounts of fructose you could only get by drinking a couple of bottles of coke everyday, will yet not be favorable for your health - even if taking fish oil can blunt the increase in hepatic de novo lipogenesis, it won't blunt the insulin resistance (Faeh. 2005).

• 

  Figure 6: Schematic representation of the main lipid metabolic pathways affected in skeletal muscle during 4 weeks of fat overfeeding. Genes indicated in white boxes were down-regulated during the dietary study, whereas genes indicated in gray boxes were up-regulated (Meugnier. 2007).

  Fat overfeeding, on the other hand, has been show to favor fat storage not just because the dietary fat can be stored without being converted to triglycerides, but also because metabolic and genomic investigations show that the lipid oxidation rate tends to decrease, and 55 genes in the skeletal muscle were modified.
  
  Modifications of which Meugnier et al. show that they stimulate the synthesis of triacylglycerol, inhibit lipolysis and reduce the oxidation of fatty acid oxidation, while promoting the development of adipocytes with an excess of only ~550kcal/day from fat per day (see Figure 6).
  
  Another potential explanation is the change in thyroid hormones, of which the data in Figure 7 from an overfeeding study by Danforth Jr., et al. (1979) tells you that the high protein overfeeding despite a 29.8% lower total energy intake triggered the most, the carbohydrate diet the 2nd most favorable (=in favor of greater energy expenditure) effects on the thyroid hormone.
  

  

  Figure 7: Effects of overfeeding with carbohydrates, fats, and protein on thyroid hormones (Danforth, Jr. 1979).

  Accordingly, high protein diets, of which we know for sure that they are the most satiating hypercaloric diets (followed by high carb and high fat | Johnstone. 1996) and have the highest thermogenic effect (see Figure 8) and can help dieters avoid the yoyo effect after a diet (Lejeune. 2005), should have the least negative impact on your physique.
  

  

  Figure 8: Estimates thermic effect of carbohydrates fats, protein, and alcohol in % energy of the energy that's ingested in form of the respective nutrients (Joosen. 2006).

  And in fact, Jose Antonio et al. (2014) have recently been able to show that a diet that contains fivefold more protein than the FDA recommends (4.4g/kg | 307g/day) is not just benign but will, in conjunction with exercise, will have significant beneficial effects on the physique of healthy resistant trained men (learn more). Furthermore studies indicate that a high protein content may also ameliorate negative effects such as an increase in intrahepatocellular lipid deposition in humans (Bortolotti. 2009).

Beware of bulking the way you did in your twenties! It's almost certainly going to make you fat, because studies indicate that age correlates with a decreased increase in energy expenditure in response to overfeeding (Roberts. 1996). Since the difference is particularly pronounced on day 1 of the respective overfeeding period (see Figure on the left), I would also refrain from excessive "refeed days" if I were 60+ years old, like the subjects in the study by Roberts et al. from which I grabbed the graph that displays the energy expenditure on a diet that contained 956kcal extra per day (phase II in this study).

• Classic overfeeding studies with protein as a single nutrient are yet unfortunately rare. Even less, namely nothing, is known about the effects of ketogenic diets, which is why it's at the moment impossible to tell whether a hypercaloric high fat diet that is devoid of carbs and low enough in protein to actually induce ketosis will have the same negative effects as a high fat diet that still contains 15-30% carbohydrates and some protein.
  Based on the studies we have, it's yet quite certain that the combination of some carbs and a high amount of fat is the most obesogenic variety of "bulking" you could possibly select. Therefore - with the exception of ketogenic diets, where corresponding data is still missing, the rule of thumb is: The more fat in the diet, the more rapid the body fat, but not necessarily the body weight gain.

• MCT overfeeding is less obesogenic - The reason that rodents that are overfed with medium-chain triglycerides (Geliebter. 1983) and assumable human beings store less fat than on long-chain triglycerides as you will find them in your bacon, sausages, dairy & co is an increase in thermogenesis that has been observed in both rodent and human studies.
  

  

  Figure 10: Metabolic rate in healthy men after the ingestion of isocaloric fat meals containing MCTs or long chain triglycerides (Hill. 1989).

  As you can see in Figure 10, this effect does not diminish over time - at least, when only the effect of the infusion of MCTs versus long-chain fatty acids is concerned. In view of the rodent study by Geliebter et al. (1983) and the results of the study by Hill et al. (1989), it appears to be quite obvious that MCTs constitute a valuable addition to hypercaloric diets. The often-heard claim that they cannot be stored as fat is yet misleading - even if they are oxidized in the liver, the increase in available energy will increase the storage of energy from other nutrients. The dream of eating as much as you want without gaining weight does therefore remain a dream - at least for all of us who don't harbor a gene defect that blunts the storage of fat.
  
  Still, in theory it would appear as if using MCTs in a dieting context makes sense. In reality, studies have shown that using MCTs as a major source of your dietary fats does not lead to significant long-term improvements in  fat or general weight loss - even if 27% of an 800kcal/day starvation diet were pure MCT oil (Yost. 1989).

Fivefold More Than the FDA Allows: Extreme High Protein Diet (4.4g/kg | 307g/day) Benign & Non-Obesogenic. Plus: Macronutrient Prescription & Changes in Food Quality | more

Alright, so what's the bottom line, then? I guess, in view of the fact that we still have few studies on high protein overfeeding and no studies on overfeeding on ketogenic diet, a conclusive bottom line cannot be reached, yet. What appears to be true, though is that a diet containing some carbohydrates and a large amounts of fat is the worst choice you can make, when you are bulking.

A protein and a high(er) carbohydrate, as well as a correspondingly low(er) fat content on the other hand, appear to be the way to go at least in the short run. In the long(er) run, on the other hand, the differences between higher fat and higher carbohydrate overfeeding appears to disappear - albeit with a small, but potentially practically significant difference in terms of the amount of body fat you will gain (see Figure 4) | Comment on Facebook!

References:

• Acheson, K. J., et al. "Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man." The American journal of clinical nutrition 48.2 (1988): 240-247. 
• Antonio, Jose, et al. "The effects of consuming a high protein diet (4.4 g/kg/d) on body composition in resistance-trained individuals." Journal of the International Society of Sports Nutrition 11.1 (2014): 19.
• Bouchard, Claude, et al. "The response to long-term overfeeding in identical twins." New England Journal of Medicine 322.21 (1990): 1477-1482. 
• Danforth Jr, E., et al. "Dietary-induced alterations in thyroid hormone metabolism during overnutrition." Journal of Clinical Investigation 64.5 (1979): 1336.
• Dirlewanger, M., et al. "Effects of short-term carbohydrate or fat overfeeding on energy expenditure and plasma leptin concentrations in healthy female subjects." International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity 24.11 (2000): 1413-1418.
• Faeh, David, et al. "Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men." Diabetes 54.7 (2005): 1907-1913.
• Forbes, Gilbert B., et al. "Hormonal response to overfeeding." The American journal of clinical nutrition 49.4 (1989): 608-611.
• Geliebter, Ae al, et al. "Overfeeding with medium-chain triglyceride diet results in diminished deposition of fat." The American journal of clinical nutrition 37.1 (1983): 1-4.
• Hill, James O., et al. "Thermogenesis in humans during overfeeding with medium-chain triglycerides." Metabolism 38.7 (1989): 641-648.
• Horton, Tracy J., et al. "Fat and carbohydrate overfeeding in humans: different effects on energy storage." The American journal of clinical nutrition 62.1 (1995): 19-29. 
• Johnstone, A. M., R. J. Stubbs, and C. G. Harbron. "Effect of overfeeding macronutrients on day-to-day food intake in man." European journal of clinical nutrition 50.7 (1996): 418-430. 
• Joosen, A. M., and Klaas R. Westerterp. "Energy expenditure during overfeeding." Nutr Metab (Lond) 3 (2006): 25.
• Kolaczynski, JERZY W., et al. "Response of leptin to short-term and prolonged overfeeding in humans." The Journal of Clinical Endocrinology & Metabolism 81.11 (1996): 4162-4165.
• Lejeune, Manuela PGM, Eva MR Kovacs, and Margriet S. Westerterp-Plantenga. "Additional protein intake limits weight regain after weight loss in humans." British Journal of Nutrition 93.02 (2005): 281-289.
• McDevitt, Regina M., et al. "Macronutrient disposal during controlled overfeeding with glucose, fructose, sucrose, or fat in lean and obese women." The American journal of clinical nutrition 72.2 (2000): 369-377.
• McDevitt, Regina M., et al. "De novo lipogenesis during controlled overfeeding with sucrose or glucose in lean and obese women." The American journal of clinical nutrition 74.6 (2001): 737-746.
• Meugnier, Emmanuelle, et al. "Changes in gene expression in skeletal muscle in response to fat overfeeding in lean men." Obesity 15.11 (2007): 2583-2594. 
• Minehira, K., et al. "Effect of carbohydrate overfeeding on whole body macronutrient metabolism and expression of lipogenic enzymes in adipose tissue of lean and overweight humans." International journal of obesity 28.10 (2004): 1291-1298.
• Poehlman, Eric T., et al. "Genotype-controlled changes in body composition and fat morphology following overfeeding in twins." The American journal of clinical nutrition 43.5 (1986): 723-731. 
• Roberts, Susan B., et al. "Effects of age on energy expenditure and substrate oxidation during experimental overfeeding in healthy men." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 51.2 (1996): B148-B157.
• Terán-García, Margarita, et al. "Effects of cholesterol ester transfer protein (CETP) gene on adiposity in response to long-term overfeeding." Atherosclerosis 196.1 (2008): 455-460.
• Ukkola, Olavi, A. Tremblay, and C. Bouchard. "Beta-2 adrenergic receptor variants are associated with subcutaneous fat accumulation in response to long-term overfeeding." International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity 25.11 (2001): 1604-1608.
• Vanltallie, Theodore B. "Resistance to weight gain during overfeeding: a NEAT explanation." Nutrition reviews 59.2 (2001): 48-51.
• Yost, Trudy J., and R. H. Eckel. "Hypocaloric feeding in obese women: metabolic effects of medium-chain triglyceride substitution." The American journal of clinical nutrition 49.2 (1989): 326-330.

Natural Sildenafil & Testosterone Alternatives: Pedalium Murex & Paederia Foetida +150% Testosterone and +200% Erectile Function. Plus: Icariin, Aromatase & Stronger Bones. Probiotics, Phytosterols & Thyroid Activity.

If the Aliens have seen these Bugarash apocalypse pilgrims, they have probably turned tail and fled ;-)

I guess the SuppVersity figure of the week was a date "12/21/2012", I mean this is a once in a life-time event! Or do you really believe there will be another chance for mankind to be snatched from the jaws of extinction?

Ok, enough of the sarcasm, the world is still there and the SuppVersity is still operating, so let's get to the not so short On Short Notice items for today.

If there had been more room in the headline I would probably have labeled it "Endocrine Special" and I guess once you have gone through the posts, you will agree that this would certainly have made sense.

• Traditional treatment of osteopenia with Epimedium brevicornum works, 'cause it's a potent aromatase promoter (Yang. 2012) -- When a group of researchers from the Chengdu Institute of Biology, Chinese Academy of Sciences and the School of Chinese Pharmacy, Chengdu University of Traditional Chinese Medicine in Chengdu, China, set out to investigate the mechanism behind the anti-osteoporotic effects of the dried leave extract from Epimedium brevicornum, they already suspected that it would probably be related to some sort of endocrine modulation.
  
  

  

  Figure 1: In vitro effect of Forskolin and Icariin on aromatase expression in KGN cells (Yang. 2012)

  With estrogen deficiency being the major cause of osteoporosis, a disease which does by the way affect over 200 million people worldwide (Riggs. 1998), being their the most likely mechanism behind the bone building and bone mineral density (BMD) protective effects, it was obvious to study, whether there was some sort of interaction between the extract and the data in figure 1 shows that Yang et al. were right to do so (note: the cell line used in the study was a KGN granulosa cell that's closely associated with the developing female oocyte, so effects could vary from one tissue to the other)
  
  Now all that certainly sounds as if this was bad stuff no sane male human being should be taking. Luckily, for many of you, my fellow men, who may have been exposed to Epimidium / Icariin from various supplements, this is not the case. Why? Simply because estrogen is not the enemy and Epimidium has not only been found to have anti-aging effects (whole extracts; Yan. 2009), it also prevents neurotoxicity from beta-amyloid plague the key feature of Alzheimer's and similar diseases (Zeng. 2010; listen to Thursday's Science Round-Up for other amyloid beta inhibitors / protectant's) and the neurotoxic effects of excess corticosteroids (Liu. 2011). In addition, Epimidium pubescen flavenoids have been shown to reverse the negative effects even passive exposure to cigarette smoke may have on the bone mineral density of male rats (Gao. 2012) and Icariin the common denominator in all of the members of the Epimidium family exerts direct proliferative and thus pro-fertility effects on the sertoli cells in male rodents (Nan. 2012).
  
  

  

  Table 1: Analysis of Chinese Epimidium species (MDida. 2010)

  Ah, and last but not least the beneficial effect Horny Goat Weed (likewise one of the members of the Epimidium family) has on male libido are likely partly a result of the increased aromatase activity, as well. If it works for you, your estrogen levels are probably pretty low to begin with (this reasoning is based on the profound beneficial effects of estrogen on male libido in men expressing little to no aromatase enzyme; Carani. 1999).

• Pedalium murex Linn. fruits may not be as potent acute libido and erectile performance enhancers as sildenafil, but the effects accumulate and persist just as its unique testosterone boosting effects (Sharma. 2012) -- In case taking a potential proestrogenic compound like Horny Goat is nothing you feel would do anything good for your libido, you may want to use some Pedalium murex Linn. in traditional Indian medicinea herb that has been used in traditional Indian medicine for centuries to treat male sexual dysfunction and impotency.
  

  

  Figure 2: Effects of different doses of an ethanolic extract from Pedalium murex (P.m.) and Sildenafil citrate (5mgkg) on penile erection scores and post ejaculatory interval (time it takes to be able to have sex again) exrpessed relative to saline treated control (based on Sharma. 2012)

  As the data in figure 2 shows, its effects on erectile performance are slightly less pronounced than those of sildenafil citrate, but at an appropriate dosage and after some time, it will probably do its job sufficiently for most men with respective problems. What's really exiting though, is that the data in figure 3 clearly shows that it does so not by simple nitric oxide effects (P. murex at 10 mg/
  ml exhibited a relative nitric oxide release of 15.3 mM as compared to a nitric oxide release of 39.3472.7 mM with sildenafil citrate), but probably (also) by boosting testosterone levels. 
  
  

  

  Figure 3: Serum testosterone levels during and after Pedalium murex or Sildenafil citrate administration expressed relative to saline control (Sharma. 2012)

  Since the testosterone levels remained elevated for 14 days after the treatment was seized these observations make P. murex a potential candidate for the next best natty test booster.to be powered by advertisement lines like "up to 125% increase in testosterone that last for more than 2 weeks" even when you take some time off. I guess, the only serious downside here is the close relation of P. murex to the notoriously useless Tribulus, which does also contain furostanol glycosides. Luckily Magnle and Jolley found another potentially active ingredient in P. murex fruit. The compound goes by the name diosgenin and appears to be a direct precursor for the synthesis of sex hormones including testosterone (Mangle. 1998).
  
  Since I don't think you will have to wait very long until the first major players in the supplement business will jump on this bandwagon - you know that a single rodent study is enough to make fortune until people realize that this stuff does not work, at all - you will probably soon be able to test it on yourself. In case you intend to do that, you should certainly look for a standardized ethanolic extract with ~20%+ of diosgenin (that was the content of the extract Sharma et al. used) and a serving size of 16.2mg/kg per body weight, the HED of the 100mg/kg group (that would be 1,300mg /day of the extract for an 80kg adult).

• Paederia foetida Linn. (P. foetida) yet another Indian libido and testosterone boosting herb (Soni. 2012) -- If you like the appeal of exclusiveness a climbing plant found in the Central and Eastern Himalayas, at elevations of up to 5000 ft, you may prefer the an ethanol extract of Paederia foetida Linn. (P. foetida) leaves over the previously discussed Pedalium murex fruit extract.
  
  

  

  Figure 4: Penile erection index and testosterone levels of rats after 15 and 28 days on P. foetida, data expressed relative to saline control (Soni. 2012)

  According to a recent study from the same group of Indian scientists (yet a different lead author), the effects of P. foetida and P. murex are in fact virtually identical. While the general protocol was very similar (in this done on rat, not mice) the positive control was not Sildenafil citrate, as in the previously mentioned experiment, but an intramuscular injection of 0.5 mg/kg body weight of testosterone suspension in arachis oil twice a week. It's actually a pity the scientists didn't measure the actual testosterone levels in the animals in the testosterone group. I would be curious how the 2.5x increase in the high dose group (200mg/kg, human equivalent ~2,600mg/day) would compare. When it comes to the erection quality, it did at least easily top the results of injectable testosterone (see figure 4), which is yet allegedly not the best erection booster, anyway. And if we went by the data on body weight and the weight of the testes, seminal vesicles, prostate glands and epididymis, it even appears to be more anabolic than testosterone; after all the body weight gain in the PF groups were 15%. 23% and 34% higher than in the control group and comparable if not higher to those that were induced by testosterone (+29%).
  
  And for all the supplement producers and fans of stacks it may be important to know that the leaves of P. foetida, which is also used as carminative, antiinflammatory, astringent, spasmolytic, antidiarrhoeal, diuretic and antilithic do contain a whole host of well- and lesser known compounds, e.g. iridoid glycosides, sitosterol, stigmasterol, campesterol, ursolic acid, hentriacontane, hentriacontanol, ceryl alcohol, palmitic acid and methyl mercaptan, but no diosgenin. So Ayurvedabol (TM) or whatever name ending on -bol, -drol or -ripp-off has not been used by the creepy competition, already, could benefit from having both Paederia foetida and Pedalium murex in it ;-)

• Combination of probiotics and phytosterols ramps up thyroid function and (re-)establishes a healthy lipid profile (Awaisheh. 2012) -- While I could offer you a minimum of two additional libido enhancing, potentially pro-anabolic testosterone booster, I know that not all of you are into these products (am I right ladies?), so I thought it prudent to close this installment of On Short Notice with a study on thyroid metabolism, which could be is of interested for all of you.
  
  
  Which phytosterols are there and where can I find them? The major phytosterols in the human diet are sitosterol (high in nuts, amaranth, avocados, grape leaves), stigmasterol (high in coriander, chocolate and soy), campesterol (high in various vegetable oils, spec. conola / rapeseed) and brassicasterol (high in cabbage, broccoli, other brassica, but also coriander, seafood and rapeseed oil).
  Contrary to some previous studies and anecdotal reports on the Internet, a recent paper by scientists from the Department of Food Science at the Al-Balqa Applied University, in Salt, Jordan, suggest that phytosterols don't have thyroid inhibiting, but promoting effects.
  
  In their latest study Awaisheh et al. investigated the effects of a probiotic stack containing two strains of each of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus gasseri, and Lactobacillus reuteri and a phytosterol supplement on the lipid metabolism in rodents. Their results show that the addition of the phytosterol supplement promoted the already pronounced effects the probiotics had on the hypercholesterolemia of the rodents who were fed with a high-fat-high-cholesterol basal diet for 8 weeks. In addition, the phytosterols, yet not the probiotics alone, elevated the levels of serum total thyroxine (TT4), total triiodothyronine (TT3), and free triiodothyronin (fT3), which could have exerted additional benefits on the non-measured triglyceride levels.
  
  These results do actually come as a surprise and I would like to see more research - specifically in human trials - before I would buy products from producers who seize the scientists suggestion that this renders probiotics and phytosterols potential candidates for "functional foods" - I mean, let's be honest ever since the first "functional foods" hit the market people have been getting sicker: Do you really believe that's because they don't eat the "good" cholesterol lowering margarine instead of their beloved Kerrygold butter? I don't think so.

That's it for today.. well, aside from the promise to include the other testosterone and libido boosting herb studies in another SuppVersity post and a selection of the latest  SuppVersity Facebook News, of course:

• Iron deficiency makes H Pylori go on a rampage - Iron deficiency enhances H. pylori virulence and increases risk of gastric cancer (read more)
• Danish folk medicine for depression? Not really, but there are a couple of promising natural MAO-A inhibitors the Danes have been using for centuries (read more)
• Strength training equally heart healthy as aerobics - 6-weeks of strength training show particular beneficial effects in African American men (read more)

Since I it's still pretty early and I am certainly not going to the city, before the shops close and all the people who believed they wouldn't need Christmas presents this year, since the world would *put whatever apocalyptic catastrophe you like here*, have gone home, I may be adding some more news later. Until then, I hope you have some fun with what's already there and are looking forward for the 2nd installment of the "Making HIIT a Hit" series that will be published tomorrow.

References:

• Awaisheh SS, Khalifeh MS, Al-Ruwaili MA, Khalil OM, Al-Ameri OH, Al-Groom R. Effect of supplementation of probiotics and phytosterols alone or in combination on serum and hepatic lipid profiles and thyroid hormones of hypercholesterolemic rats. J Dairy Sci. 2012 Nov 22.
• Carani C, Rochira V, Faustini-Fustini M, Balestrieri A, Granata AR. Role of oestrogen in male sexual behaviour: insights from the natural model of aromatase deficiency. Clin Endocrinol (Oxf). 1999 Oct;51(4):517-24.
• Gao SG, Liu H, Li KH, Liu WH, Xu M, Jiang W, Wei LC, Zhang FJ, Tian J, Xiao WF, Yang Y, Song Y, Lei GH. Effect of Epimedium pubescen flavonoid on bone mineral density and biomechanical properties of femoral distal end and femoral diaphysis of passively smoking male rats. J Orthop Sci. 2012 May;17(3):281-8.
• Liu B, Zhang H, Xu C, Yang G, Tao J, Huang J, Wu J, Duan X, Cao Y, Dong J. Neuroprotective effects of icariin on corticosterone-induced apoptosis in primary cultured rat hippocampal neurons. Brain Res. 2011 Feb 23;1375:59-67. 
• Mangle MS, Jolley CI. HPTLC studies on Tribulus terrestris (Chota ghokru) and Pedalium murex (Bada ghokru). Indian Drugs. 1998; 35:189–194.
• MDidea Extracts Professional. Horny Goat Weed or Epimedium Herb: Botanical Origin, Archeology, Traditional and Pharmacological findings of Epimedium species, fractions and isolated components. 08th, Oct. 2010. < http://www.mdidea.net/products/herbextract/icariin/data10.html > retrieved on 12/21/2012. 
• Nan Y, Zhang X, Yang G, Xie J, Lu Z, Wang W, Ni X, Cao X, Ma J, Wang Z. Icariin stimulates the proliferation of rat Sertoli cells in an ERK1/2-dependent manner in vitro. Andrologia. 2012 Nov 7.
• Riggs BL, Khosla S, Melton LJ 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. 1998 May;13(5):763-73. 
• Sharma V, Thakur M, Dixit VK. A comparative study of ethanolic extracts of Pedalium murex Linn. fruits and sildenafil citrate on sexual behaviors and serum testosterone level in male rats during and after treatment. J Ethnopharmacol. 2012 Aug 30;143(1):201-6.
• Soni DK, Sharma V, Chauhan NS, Dixit VK. Effect of ethanolic extract of Paederia foetida Linn. leaves on sexual behavior and spermatogenesis in male rats
• Yan S, Wu B, Lin Z, Jin H, Huang J, Yang Y, Zhang X, Shen Z, Zhang W. Metabonomic characterization of aging and investigation on the anti-aging effects of total flavones of Epimedium. Mol Biosyst. 2009 Oct;5(10):1204-13.
• Zeng KW, Ko H, Yang HO, Wang XM. Icariin attenuates β-amyloid-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells. Neuropharmacology. 2010 Nov;59(6):542-50.

Complete Meals & GI (Non-)Sense, Glutamine & GLP-1, Low Thyroid & High Trigs, N-3 vs. N-6 Interactions, Optimal DHA Dosage in Kids W/ NAFLD, Selenium vs. Aluminum Toxicity

While this is not the exact combination of chicken breast, mashed potatoes and salad in the first one of today's news items, it's more than likely that the predicted GI (and thus probably what you would find if you looked it up in a table) overestimates the postprandial glucose response to this meal by ~50% and says absolutely nothing about the insulin response. It looks like complex meals and over-simplified theories, don't mix well, at all ;-)

78% that's the SuppVersity Figure of the Week and actually part of the additional information I provided on one of today's On Short Notice items. It's the increase in coronary heart disease risk women with subclinical hypothyroidism have compared to their peers with spot on TSH levels of 0.5-1.5mU/L (Asvold. 2012). In conjunction with other more or less recent studies, such as Mitchel's, Hsu's and Sahai's paper confirming the previously often talked about but not well-established 2-fold increase in congenital hypothyroidism from the early 1990s to the first years of the new millennium (Mitchel 2011), the predictive value of high TSH levels in the first trimester (early pregnancy hypothyroidism) for adverse pregnancy outcomes (Schneuer. 2012), the 30% risk increase in all-cause mortality in both women and men with subclinical hypothyroidism Tseng et al. reported in their paper earlier this year or the impairment of spatial working memory (Yin. 2012), Asvold's results only add to the evidence that the potential pitfalls of an increasingly prevalent metabolic dysfunction may have been ignored way too long.

• More GI lovin' - On the menu today: Mashed potaoes with chicken, rapeseed oil or both (Hätönen. 2011) - I thought a mini-follow-up on Friday's post on the GI would be nice, 'cause some of you have not without reason been complaining that not everyone would eat pure white bread, like my students do.
  
  

  

  Figure 1: The real (=measured) GI of a meal does differ significantly from the theoretical prediction. So, even if the concept was worth bothering, the GIs of complete meals simply wrong, if they are not measured (Hötönen. 2011).

  Moreover, the mere fact that the scientists from the Department of Lifestyles and Participation at the National Institute for Health and Welfare in Helsinki, Finland, found that the addition of chicken breast, rapeseed oil and a salad, individually and in combination, had the GI of a meal containing six mashed potatoes (this was the parameter that was held constant) induced more than twofold changes in GI, with the addition of chicken breast having the greatest deviation from the predicted value in this group of 11 (initially 12) healthy subjects, three men and nine women, aged 36.2 (SD 14.1) years with a BMI of 21.3 (SD 1.7) kg/m² and normal glucose tolerance (see figure 1).
  
  Now given the fact that most data on the GI of complete meals has never been measured, but is actually based on the same predictions the scientists used, it stands to reason that...
  

  [...] this highlights the problems encountered when predicting the GI values of mixed meals. The protein com-ponent of the mixed meal evoked the largest insulinaemic responses and markedly increased the II of the mixed meal containing protein. However, introducing fat into the meal decreased the effect of protein on the insulinaemic responses (Hätönen. 2011)

  So, this does not simply bust the idea that you could calculate the GI, it does likewise show you that people who are still overtly scared of insulin (which is hillarious as long as you are insulin sensitive) are doing he exact wrong thing, when they make food-choices based on GI: Whey protein would in that case be in as much a no-go as simply eating a chicken breast with your mashed potatoes would be, because other than what most people believe, it does increase the insulin spike and thus reduce the glycemic index by allowing your body to clear the glucose more efficiently from the circulation.
  
  Suggested reads: The red box in the "Whey is More Insulinogenic than White Bread" post on the partitioning effects of BCAAs and yesterday's Facebook post on the anti-Alzheimer's effects of insulin.

• 

  Suggested read: Amino Acids for Super Humans the purported ergogenic effects of l-glutamine

  30g of oral glutamine have similar effects on GLP-1 as 75g of glucose (Greenfield. 2008) - Still a follow up on the GI discussion, I think you may be interested in. If you are someone who follows the questionable practice of ingesting large boluses of glutamine in the futile believe that this would increase your gains or speed up recovery, you may be pleased to hear that only 30g of oral l-glutamine produced an increase in the "Fat Burning Satiety Hormone GLP-1" (read more on GLP-1) that's on a gram to gram basis more pronounced than in response to insulin (0.41pmol/L per gram glucose vs. 0.75pmol/L per gram of glutamine; in 8 healthy subjects).
  
  Before you go and buy tons of glutamine, you should however consider that GIP, the pro-insulinogenic peptide and glucagon (ramps up gluconeogenesis in the liver) were likewise increased by the ingestion of this bolus of glutamine. It is therefore no wonder that glutamine has never been shown to be a "fat burner". Nonetheless, a 1999 study by Bowtell et al. would suggest that it may come handy to replenish liver and muscle glycogen after a workout (8g alone did increase glucose storage after a workout to a similar degree as a 18.5% glucose polymer solution and additional 25% glucose storage mostly in the liver, when both were coingested; cf. Bowtell. 1999). And if you don't care about that - your gut integrity could also be a reason to consider supplementation in the vicinity of particular strenuous or length workouts (see "Shedding Some Light on the Leaky Gut <> Exercise Connection") 

• Practical relevance? Based on data from a 12-year longitudinal study, even women with subclinical hypothyroidism have 76% risk for coronary heart disease (p = 0.005), than women with spot on TSH levels of 0.5-1.5mU/L (Asvold. 2012). And even women well within in the "normal range" (TSH of 1.5-2.4mU/l) have a 41% higher risk of heart disease, although this is only borderline significant (p = 0.08). For men the TSH level alone had not predictive value. Spec. w/ regards to T3, there are also reports of increased incidence of ventricular disfuntion (Cassetti. 2009), increased cardiac death in CVD patients (Iervasi. 2003) and impaired recovery after a stroke (Alevizaki. 2007). We do yet have to be cautious, here as "low T3" syndrome could as well be the consequence of overall inflammation and the association does not tell us anything about what's the chicken and the egg.
  Low thyroid, high triglyceride (Hashimoto. 2012) -- If you are wondering why on earth your trigs won't come down, it may well be that it's the absence of sufficient amounts of thyroid hormone. I a soon-to-be-published paper in Endocrinology scientists from the Gunma University in Maebashi, Gunma, Japan, report that thyroid hormone regulates the expression of a Stearoyl-CoA desaturase-1 (SCD-1) which controls the production of trigs from carbohydrates.
  
  Surprisingly the 75% increase due to hypothyroidism and the 75% decrease in SCD-1 mRNA expression (both compared to a euthyroid state) the scientists observed in rodents in response to the administration of T3 were not mediated by receptor binding, but simply as a down-stream effect of direct modifications of the SCD-1 gene promoter between -124 and -92 bp by T3.
  
  On a related side note: It is actually the last mentioned mechanism which is the major new finding in the study at hand and not the fact that T3 can reduce the conversion of carbohydrates to triglicerides that is the actual news here. After all, the latter is something scientist should know, but obviously like to forget about ever since the late 1999s (Waters. 1997)

• Omega-6 intake and not low omega-3 intake is the problem (Liou. 2007) -- Another older study, but one I am posting in response to a discussion some of you are having about omega-3 (ALA) intake in the post about safflower oil and DHT, because I simply feel that it's necessary to shed some light  on the erroneous assumption that by simply upping your intake of omega-3s or fish oil intake you could get away without decreasing your omega-6 intake, which in and out of itself will already increase the amount of anti-inflammatory omega-3 fatty acids (supplementation of DHA can still be advisable, specifically if you are a vegetarian).
  
  

  

  Figure 2: Effect of 4 weeks of high (red) vs. 4 weeks of low (green) linoleic acid (n-6) intake on short and long-chain omega-3 plasma phospholipid content in healthy men (Liou. 2007)

  In 2007, already Liu et al. conducted a very interesting experiment in the course of which they fed healthy men diets with identical amounts of omega-3 fatty acids (1% of the total energy intake), but two different amounts of linoleic acid (omega-6) and found that the high omega-6 intake (10.1% vs. 3.8% of the total energy intake) alone decreased the total amount of EPA among the plasma phospholipids (the major long-chain omega-3 fatty acid in fish oil), not just the ratio of omega-3 to omega-6, in the blood of their 29-45 year-old subjects by more than 25% (see figure 2). The paradoxical effect on DHA, on the other hand, would warrant further investigation, and underlines how reliant we are - if anything on the intake of pure DHA, which dropped in consequence to the test diet, which was devoid of fatty fish, while the original diet of the non-vegetarian subjects had fish in it.
  
  In this context, I would also like to point out that DHA is exactly where real fish is far superior to fish oil caps, because it has a way more favorable EPA:DHA ratio than fish oil caps. Salmon fillets for example have - depending on the fatty acid source in the diet 8.5g : 13.8g, 4.4g : 7.8g and 1.5g : 2.9g (all values per 100g) when the feed contains fish oil, fish and rapeseed and fish + rapeseed and rapeseed, only.
  
  And while the ratios are similar regardless of the chow, the data from the Seierstad et al. clearly shows that the fatty acid content of the diets can induce almost 5-fold differences in terms of the total DHA content and the omega-3 to omega 6 ratio (fish oil diet: 6.5, fish oil + rapeseed: 1.7, rapeseed: 0.6) of salmon fillets (Seierstad. 2003). 

• It does not take much: 500mg DHA not more effective than 250mg  (Nobili. 2012) -- At least if it comes to its beneficial effects against liver steatosis in children  (mean age 11 years; BMI 26.6kg/m² and 24.4kg/m², in the low and high dose groups respectively with with NAFLD, the amount of DHA does not appear to be so important. According to the results of their 2-year registered controlled trial, both 250mg and 500mg of Docosahexaenoic acid lead to identical and profound reductions in the odds ratio of developing more severe steatosis during the study period.
  
  

  

  Figure 3: Odds ratio (comparing DHA supplement vs. placebo) of more severe vs. less severe liver steatosis determined every 6 months during the 24-month study period (Nobili. 2012)

  If you take a closer look at the data in figure 3, you will even have to concede that the lower dosage did a better job - while the mean odds ratios were only marginally lower in the 250mg DHA group, the extremely high standard deviations in the 500mg DHA would suggest that the 250mg dose appears to be more reliable. In this regard it may be interesting that the increase in serum DHA did mirror the dosages. With a 0.65% and 1.15% increase in DHA those were about 2x higher in the 20 boys and girls in the high dose group compared to the 20 kids in the control group who received a 290 mg linoleic acid germ oil supplement "placebo" (by the way, a monosaturated fatty acid placebo would have been more of a placebo than 290mg of omega-6)
  
  In view of the fact that the changes in triglycerides, ALT, HOMA-IR and BMI (which was not even different from the placebo group) were likewise identical, it does not appear as if anything that goes beyond the amount you will find in 2x cheap fish oil caps, or 10g even of the cheapest salmon fillet (see last paragraph of previous item) would be necessary to ellicit the anti-steatosis effect of fish oil - since those kids weight on average 55kg, an adult may want to add in another fish oil cap to get up to 360mg DHA per day or simply eat his fatty fish once or twice a week.

• Selenium ameliorates aluminum toxicity (Viezeliene. 2012) -- With the whole upheaval about the potential negative side effects of the aluminum in vaccines, the formerly overlooked yet well-known neurotoxic (Exley. 1992; Gupta. 2005), hepatotoxic (Abubakar. 2003; Perez. 2005) and nephrotoxic metal (Geyikoglu. 2012) has all of a sudden returned to the center of public interest.
  
  Therefore I thought that you will be interested in the results of a study that's going to be published in the next issue of the Journal of Trace Elements in Medicine and Biology - irrespective of whether you believe, like Tomljenovic and Shaw that
  

  "the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community"(Tomljenovic. 2011)

  After all, vaccines are not the only potential source of aluminum in our environment, so that the ameliorative effects (all values remained normal in the aluminum exposed group, while there were 30%, 55% and 42% increases in GSH in the animals who received only the selenium injection) the co-administration of supplemental selenium had on the GSH reductions in liver, kidney and brain of Balb/c mice weighing 20–25g who were exposed (by i.p. injection)to AlCl3 (25 mg Al(3+)/kg body mass) for 16h could be important, regardless of whether you do or don't intend to get vaccinated.
  
  

  

  There is more about selenium at the SuppVersity, for example on its pro-fertility effects, and its anti-corrosive effects in the brain.

  That said, the dosage requirements necessary to maintain healthy GSH levels are probably much lower than the hillarious (for a healthy individual) in the study at hand 1,250µg/kg body weight of sodium selenite (Na2SeO3). Considering the elemental selenium content in Na2SeO3, the latter would equal to ~3,650µg - unquestionably WAY too much (remember this was a one-time dosage that was specifically co-administered w/ the aluminum). Even the 'no observed adverse effect' level for a 70kg man of intake which is ~1000µg/d (Whanger. 1999) appears unnecessarily high, so that the consumption of a handful of brazil nuts once or twice a week and/or other high selenium foods such as tuna, cod, oysters, shrimp, but also eggs, meats, poultry, mushroom and onions on a regular should suffice to get what you need, to fortify yourself against the constant assault of heavy metals.
  
  What would be interesting, though, is a study into the effects of adding selenium to the "safe" aluminum in vaccines. I mean, you cannot seriously tell me that we could not afford doing that and if it reduced any toxicity issues, why not?

That's about it for today, I did not post all too many new facebook news as of yet (I mean, come on, it's Saturday ;-), but if you are into medicinal horror-stories, you will certainly like the story about the flesh eating killer fungus. If you prefer microbes over fungi, you are probably better off with the latest insights into the associations of certain gutbacteria with the incidence of stroke. And if you are more into other aspects of the digestive tract you may be interested in the effects of gastric emptying time on postprandial gylcemia and insulin release.

If none of those news is to your liking, I suggest you either wait for me to post something else (could be happening within the next hours at www.facebook.com/SuppVersity), or simply enjoy the weekend and come back tomorrow when you are rested for another (hopefully) enlightening SuppVersity post.

References:

• Abubakar  MG,  Taylor  A,  Ferns  GA.  Aluminium  administration  is  associated  with enhanced  hepatic  oxidant  stress  that  may  be  offset  by  dietary  vitamin  E  in  the rat. Int J Exp Pathol 2003;84:49–54.
• Asvold BO, Bjøro T, Platou C, Vatten LJ. Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT Study in Norway. Clin Endocrinol (Oxf). 2012 Dec;77(6):911-7.
• Bowtell JL, Gelly K, Jackman ML, Patel A, Simeoni M, Rennie MJ. Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise. J Appl Physiol. 1999 Jun;86(6):1770-7.
• Cassetti G, Pinelli M, Bindi M, Bianchi M, Castiglioni M. [Low T3 syndrome and left ventricular diastolic function]. G Ital Cardiol (Rome). 2009 Aug;10(8):553-7. 
• Exley  C,  Birchall  JD.  The  cellular  toxicity  of  aluminium.  J  Theor  Biol 1992;159:83–98.
• Geyikoglu  F,  Turkez  H,  Ozhan  Bakir  T,  Cicek  M.  The  genotoxic,  hepa- totoxic,  nephrotoxic,  haematotoxic  and  histopathological  effects  in  rats after aluminium chronic intoxication. Toxicol Ind Health 2012;15.
• Greenfield JR, Farooqi IS, Keogh JM, Henning E, Habib AM, Blackwood A, Reimann F, Holst JJ, Gribble FM. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr. 2009 Jan;89(1):106-13.
• Gupta  VB,  Anitha  S,  Hegde  ML,  Zecca  L,  Garruto  RM,  Ravid  R,  et  al.  Alu- minium  in  Alzheimer’s  disease:  are  we  still  at  a  crossroad?  Cell  Mol  Life  Sci 2005;62:143–58.
• Hashimoto K, Ishida E, Miura A, Ozawa A, Shibusawa N, Satoh T, Okada S, Yamada M, Mori M. Human Stearoyl-CoA Desaturase 1 (SCD-1) Gene Expression Is Negatively Regulated by Thyroid Hormone without Direct Binding of Thyroid Hormone Receptor to the Gene Promoter. Endocrinology. 2012 Dec 7.
• Hätönen KA, Virtamo J, Eriksson JG, Sinkko HK, Sundvall JE, Valsta LM. Protein and fat modify the glycaemic and insulinaemic responses to a mashed potato-based meal. Br J Nutr. 2011 Jul;106(2):248-53. 
• Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L'Abbate A, Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003 Feb 11;107(5):708-13.
• Liou YA, King DJ, Zibrik D, Innis SM. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr. 2007 Apr;137(4):945-52. 
• Mitchell ML, Hsu HW, Sahai I; Massachusetts Pediatric Endocrine Work Group. The increased incidence of congenital hypothyroidism: fact or fancy? Clin Endocrinol (Oxf). 2011 Dec;75(6):806-10.
• Perez  G,  Pregi  N,  Vittori  D,  Di  Risio  C,  Garbossa  G,  Nesse  A.  Aluminium  expo- sure  affects  transferrin-dependent  and  -independent  iron  uptake  by  K562  cells. Biochim  Biophys  Acta  2005;1745:124–30. 
• Schneuer FJ, Nassar N, Tasevski V, Morris JM, Roberts CL. Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes. J Clin Endocrinol Metab. 2012 Sep;97(9):3115-22.
• Seierstad SL, Seljeflot I, Johansen O, Hansen R, Haugen M, Rosenlund G, Frøyland L, Arnesen H. Dietary intake of differently fed salmon; the influence on markers of human atherosclerosis. Eur J Clin Invest. 2005 Jan;35(1):52-9.
• Waters KM, Miller CW, Ntambi JM. Localization of a negative thyroid hormone-response region in hepatic stearoyl-CoA desaturase gene 1. Biochem Biophys Res Commun. 1997 Apr 28;233(3):838-43. 
• Whanger P, Vendeland S, Park Y-C & Xia Y. Metabolism of sub-toxic levels of selenium in animals and humans. Annals of Clinical Laboratory Science. 1996;26, 99-113.

Fructose as a Dieting Tool: 100g Fructose Per Day Exert Sign. Protein Sparing Effects & Ameliorate the Decline in Thyroid Hormones During Starvation Diet in the Obese

Fructose as an injectable Dieting Aid? Sounds crazy, but it works!

Would you ever have remotely considered that a high-fructose corn-syrup based sugar-sweetened beverage could help seven health obese women who are 35%-90% over their ideal weight lose weight? No, ...?

Well, honestly, me neither and if we take a closer look at the experimental design of a 1986 study by Robert A. Gelfand and Robert S. Sherwin from the prestigious Yale University, we will have to relativize the aforementioned claim. Coke alone may not do the trick. Pure fructose, if it's infused right into the bloodstream, on the other hand will "abolishes the entire hormone-substrate response to fasting, and spares body protein without raising insulin above postabsorptive levels." (Gelfand. 1986)

Learn more about fructose at the SuppVersity

Bad Fructose not so Bad, After All! Learn its Benefits.

Fructose From Fruit is NOT the Problem

Americans Don't Eat More Fructose These Days!

An Apple A Day, Keeps... & More (Guestpost)

Fructose is Not Worse Than Sugar

The Obesogenic Fructose Fat Connection

Before we are pondering the results, let's first have a closer look at the actual design of a study was conducted to "examine the influence of low-dose fructose infusion on nitrogen economy and the metabolic response to fasting in man" (Gelfand. 1986 | I know that you should do that in "man", not rodents, but that's costly and has the aforementioned limitations).

To this ends, the aforementioned overweight to obese women who were not diabetic and normal blood glucose and insulin levels, had normal thyroid and liver function and had been consuming a weight maintenance diet with at least 200g of carbohydrates per day before they were recruited for the study, were fasted for a period of 10 days (they did get a multivitamin, a folic acid and a potassium chloride tablet to eat, though ;-) and randomly divided into 2 groups using a crossover design:

• Group 1 (n = 4) received intravenous fructose during the last 3 days of the IO-day fasting period, while 
• Group 2 (n = 3) received fructose for the initial 7 days of the fast 

In all subjects, fructose was administered by continuous intravenous infusion of a 10% solution in water (American McGaw), delivering 100 g of fructose (375 kcal) per day.

Figure 1: Changes in plasma glucose and insulin (left) and active thyroid hormone T3 (right) during the fast with and without fructose (Gelfand. 1986)

As you can see in Figure 1 the first thing the fructose did was to keep the blood sugar and insulin stable and the levels of the active thyroid hormone T3 (iodothyronine) from plummeting. In addition, the levels of the glycogen liberating hunger hormone glucagon remained stable over the course of the whole study period in the fructose arm(s) of the study, while it increased by more than 80% in the women who didn't receive the fructose infusion.

Hormonal changes and real world effects!

Now hormonal changes are one thing. Real world effects which cannot always be predicted solely by endocrine parameters are yet often a whole different animal. What you would maybe have expected, though, is the decrease in ketone production during the supplement phases, which are indicative of "less starvation" (Blood beta-hydroxybutyrate is only a sign positive ketosis, when you actually eat tons of fat, not when you fast - in that case they are a starvation response; see Table 1)?

Table 1: Inhibitory Effect of Fructose on Starvation-Induced Ketosis. FFA Elevation,
Acidosis. and Hyperuricemia (Gelfand. 1986)

What you probably also expected are are the decreases in bicarbonate and increases in uric acid, of which the latter have previously been reported to contribute to the metabolic derangements that occur with high fructose intakes on top of an already obesogenic diet (Sahebjami. 1971; Nakagawa. 2006).

Figure 2: Urinary ammonium loss with sodium bicarbonate (G2) or potassium + calcium carbonate (G3) vs. no buffer (G1) on a 93g all protein starvation diet (Gougeon-Reyburn. 1991)

Did you know that the addition of sodium bicarbonate or a combination of potassium bicarbonate and calcium carbonate can "buffer" the increased acidity that occurs on very low energy diets and minimize the urinary nitrogen loss in form of ammonia (see Figure 2)? No, well... I guess it's about time you learn more about sodium bicarbonate, then ;-) It can, for example, also buffer the reduction in growth hormone production that occurs, when the acid level in your body is rising (see Figure 3 in previous article). Plus: It's obviously a neat ergogenic.

What is way more important than the previously described changes in serum parameters is the effect the infusion of fructose had on the energy expenditure, of which all of you know that it plummets, when you starve yourself. An effect that has long been touted as the main "risk factor for body-weight gain" (Ravussin. 1988) and thus unsuccessful dieting by scientists.

One of the factors that contributes to the "reduced rate of energy expenditure" is the the previously mentioned decline in thyroid hormone levels, of which you've just learned that it can be ameliorated by fructose injections (see Figure 1). Another one that is partly related to the decline in T3 is the loss of muscle mass - a process of which Byerley et al. (1996) argue showed that it does not have the protein sparing effects many people believe it would have.

Figure 3: Fructose decreases the total urinary nitrogen loss by ~40% (Gelfand. 1986).

In view of the results of Byerley & Heber's human study that investigated the metabolic effects of triiodothyronine replacement during fasting in obese subjects and found no effects when the protein intake was >70g/day (or 50g were complemented by 76g carbohydrates), it is thus much less surprising that the provision of fructose increased the triiodothyronine levels and decreased theh net urinary protein loss. A brief look at the serum amino acid levels of the subjects (not shown in Figure 3) suggests that fructose may have had a BCAA sparing effect, as well.

Bad Fructose? Increased Glycogen Synthesis, Reduced Glycemia, Higher Glucose Oxidation - When Do These Beneficial Effects Occur? And Why Don't They Prevail? | Read more!

Bottom line: Overall, it is unquestionably remarkable how effectively less than 375kcal of energy from fructose can reverse major components of the starvation response in human beings, i.e. abolishes the entire hormone-substrate response (specifically the decline in T3), spare body protein, and reduce urinary mineral (specifically sodium) loss.

Unfortunately, one very important question remains: What will happen if the fructose has to pass by the liver first, i.e. if it is ingested orally, not injected? 

The absence of corresponding research and the question, whether the same effects will be observed if small amounts of fructose are added to a saner form of "crash dieting", e.g. a protein modified fast, make the results of the study at hand interesting, but difficult to interpret.

References:

• Byerley, L. O., and D. Heber. "Metabolic effects of triiodothyronine replacement during fasting in obese subjects." The Journal of Clinical Endocrinology & Metabolism 81.3 (1996): 968-976. 
• Gelfand, Robert A., and Robert S. Sherwin. "Nitrogen conservation in starvation revisited: Protein sparing with intravenous fructose." Metabolism 35.1 (1986): 37-44.
• Gougeon-Reyburn, Réjeanne, François Larivière, And Errol B. Marliss. "Effects Of Bicarbonate Supplementation On Urinary Mineral Excretion During Very Low Energy Diets." The American Journal Of The Medical Sciences 302.2 (1991): 67-74.
• Nakagawa, Takahiko, et al. "A causal role for uric acid in fructose-induced metabolic syndrome." American Journal of Physiology-Renal Physiology 290.3 (2006): F625-F631.
• Ravussin, Eric, et al. "Reduced rate of energy expenditure as a risk factor for body-weight gain." New England Journal of Medicine 318.8 (1988): 467-472.
• Sahebjami, Hamid, and Raymond Scalettar. "Effects of fructose infusion on lactate and uric acid metabolism." The Lancet 297.7695 (1971): 366-369.

High Dose 3,5-Diiodo-L-Thyronine (T2) Has Similar Side Effects as Regular Thyroid Hormones: Natural Thyroid Hormone Production ￬ , Myocardial Stress ￪, Heart Weight ￪

No, the rodents had "only" enlarged hearts, but hairloss is a common side effect of elevated thyroid hormones and could theoretically occur in the long run.

You have read about it on the SuppVersity and you've seen it as an ingredient in several recent fat burners... a purportedly 100% save non-suppressive thyroid hormone which goes by the name 3,5-Diiodo-L-Thyronine (T2).

While previous rodent studies highlighted only the beneficial metabolic effects, i.e. increases in fatty acid oxidation and resting energy expenditure, a recent study from the German Institute of Human Nutrition Potsdam-Rehbruecke raises serious concerns about what Wenke Jonas and her colleagues call the "indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity" (Jonas. 2014) - in other words: About using T2 as a weight loss supplement or anti-obesity drug in lean or obese individuals without medical supervision.

Overtraining puts you at a similar risk of low T3 levels as T2 (ab)use

Female Athletes' Body Comp Suf- fers From Dieting

Female Athlete's Triad is not ex- clusively female

Female Athlete's Triad - A Vicious Cycle

Female Athlete's Triad - Recovery Part 1/3

Female Athlete's Triad - Recovery Part 2/3

Female Athlete's Triad - Recovery Part 3/3

But what exactly is it, the scientists are concerned about? In their latest rodent study (there is as of now a scarcity of human studies on "T2") the German scientists observed dose-dependent thyromimetic effects of 3,5-T2 akin to those of T3 in diet-induced obese male C57BL/6J mice.

Figure 1: The study clearly indicates that the administration of T2 leads to highly significant reductions in serum T4 and serum T3 - one thing appears to be certain: T2 is not without side effects (data from Jonas. 2014)

That's in contrast to early studies which claimed that T2 had no thyromimetic effects on hypothalamus-pituitary-thyroid axis, but would act only peripherally to increase resting energy expenditure and fat oxidation, but in line with a rodent study by Padron et al. (2014) who reported only recently that Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid sensitive tissues of rats.

Maybe the dosage is just too high? Possible, but in view of the fact that the study reports a dose dependent increase in total energy expenditure that peaks at 14% with the high dose that was used in the study at hand, using less would be pointless anyways.

On the other hand, previous studies with only 300mcg of T2 per day showed no effect on T3 & T4 levels and a small but significant weight loss in two obese subjects with normal thyroid function (Antonelli. 2010). With N=2 the number of subject in this study from a (imho) non-peer-reviewed publication you cannot access online is yet far to low to call the results representative. Moreover, it is at least somewhat disturbing that all the beneficial research on T2 comes from Department of Internal Medicine at the University of Pisa, while other labs consistently find negative side effects.

As you can see in Figure 1, this claim is 100% unwarranted, the adminstration of 2.6µg/g body weight (since the standard calculations for human equivalent doses didn't work in previous studies on real thyroid hormones, I am not even attempting to give you the human equivalent) was not without consequences on the levels of the "classic" thyroid hormones T4 (thyroxine) and T3 (triiodothyronine) in the male C57BL/6J mice.

Figure 2: Despite the increase in energy expenditure the obese rodents didn't lose weight - they simply ate more.

Now, if the goal is to increase the fat oxidation and basal energy expenditure, this probably wouldn't matter, if you decide to stay "on" forever (if you don't you would to wait at least a couple of days for your natural thyroid production to kick in, again) and, more importantly, if these changes had nothing but beneficial consequences.

Unfortunately, Jonas et al. didn't just find that the hepatic thyroid target genes involved in lipid metabol were elevated to a similar extent as you would see it with T3, they did also find that the heart weight of the mice was significantly increased (just like you would see it with T3, again) after 28 days "on" T2.

And as if that wasn't bad enough, the increased appetite that's characteristic of the hyperthyroid state the rodents were in triggered an increase in food intake which rendered the increase in energy expenditure void and 12% increase in total energy expenditure void and kept the weight of the pre-fattened and thus obese mice stable.

In view of the latest results, I would actually have to rewrite all previous SuppVersity articles. I mean, I clearly wouldn't suggest it as a tool for lean bulking any longer.

Bottom line: As the scientists point out in their previously cited conclusion, the study at hand clearly "raise[s] concern about indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity" (Jonas. 2014).

This does not mean that you cannot use T2 as a weight loss tool, but in fact of the previously mentioned absence of human data that would indicate that it does even work and considering the fact that the study at hand clearly indicates that it has similar same side effects as T3 (shut down of natural thyroid hormone production, increased heart weight indicative of myocardial stress) you could just as well use "real" thyroid hormones instead of 3,5-Diiodo-L-Thyronine (T2) if you are willing to live with the risk of side effects... or do you disagree? What are your thoughts and experiences? Let us know on the SuppVersity Facebook Page.

References:

• Antonelli, A., et al. "3, 5-diiodo-L-thyronine increases resting metabolic rate and reduces body weight without undesirable side effects." Journal of biological regulators and homeostatic agents 25.4 (2010): 655-660.
• Jonas, Wenke, et al. "3, 5-Diiodo-L-thyronine (3, 5-T2) exerts thyromimetic effects on hypothalamus-pituitary-thyroid axis, body composition, and energy metabolism in male dietinduced obese mice." Endocrinology (2014).
• Padron AS, Neto RAL, Pantaleão TU, de Souza Dos Santos MC, Araujo RL, de Andrade BM, da Silva Leandro M, de Castro JPSW, Ferreira ACF, de Carvalho DP. Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid sensitive tissues. J Endocrinol. 221.3 (2014):415–27