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.

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• 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.

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

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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

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Female Athlete's Triad - Recovery Part 1/3

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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

Thyroid Issues? Low Energy Intake Triggers Low T3 / High rT3 Syndrome in Exercising Women >19kcal/kg LBM Avail. Energy Required. Low Carbing Worsens the Impact of ED

It's not your thyroid, but your behavior that's to blame for your low T3 levels, the fatigue and being "unable to lose weight". If you exercised less and ate more, you could fix it without medical intervention or thyroid madness using Lugol's or other junk ;-)

It's something I am facing on a daily basis - on Facebook, in Emails and private messages: Women with self-induced thyroid issue who wonder that their body does everything to conserve lean and fat mass. Women who are working out on a daily basis, dieting like crazy and (in their words) "still not losing weight".

It does not take a thyroid expert to identify the reason for their problems: They are training too much and eating too little. Just like the 27 women in seminal experiment that was conducted at the Ohio University in the early 1990s. A study I am going to elaborate on in today's SuppVersity article, although I personally believe it shouldn't take experimental evidence to convince people (yes, this is true for men, as well) to stop run themselves into the ground.

Low T3 syndrome is also a part of the (Female) Athletes Triad.

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

Said study was conducted by Anne B. Loucks and Edward M. Heath who worked at the Derpartment of Biological Sciences and the College of Osteopathic Medicine at the Ohio University back in 1994. The purpose of their study was to characterize the functional relationship between energy availability and thyroid metabolism to gain insight into the extent of he dietary reform that might be necessary. The scientists expected to find a proportional relationship that would prove the necessity of dietary compensation for exercise energy expenditure to prevent reductions in T3 levels, scientists call "low T3 syndrome".

To this ends, Loucks & Heath recruited 28 healthy, non-obese, nonsmoking women (18-29 years old) with no recent history of dieting or weight loss were recruited from the university and surrounding community. All received a detailed verbal and written description of the study and signed an informed consent document. The participants had to keep a prospective diet records for seven consecutive days a measure that was necessary to determine their baseline energy intake and
Subjects were assigned to four groups in a monotonic experimental design of energy availability treatments.

Figure 1: Overview of the experimental design (Loucks. 1994)

"The experimental manipulation of dietary energy intake, exercise energy expenditure, and, thereby, energy availability (defined as dietary energy intake minus energy expenditure during exercise) is shown in Fig. 1. All four experimental groups expended ~30 kcal kg LBM of energy in daily exercise at 70% of aerobic capacity for four consecutive days beginning on day 2, 3,4, or 5 of the menstrual cycle. All exercise was performed under continuous supervision on treadmill and cycle ergometers in a sequence of 30-min bouts interrupted by lo-min rest periods."  (Loucks. 1994)

During the first exercise bout, heart rate at 70% aerobic capacity was determined by monitoring oxygen uptake. Thereafter, heart rate was monitored continuously by means of a Uniq HeartWatch model 8799 (Computer Instruments, Hemstead, NY) and maintained at the previously measured level by adjusting treadmill speed and slope or cycle work load.

I know you will be asking, but aside from simply eating more there is no way to cure low T3 symptom. In fact the worst thing you can do is to get a script for T4 from your doc, because this will only elevate the inactive thyroid hormone (=break) rT3.

If the heart rate began to drift monotonically, suggesting a thermoregulatory effect, then oxygen uptake was measured directly by gas analysis. Heart rate and Borg scores of per- ceived exertion were recorded at the fourth and fifth minutes of each exercise bout.

Figure 2: Energy intake and expenditure (kcal/lbm) during the study period in all four grous (Loucks. 1999)

As you can see in Figure 2 the amount of available energy ranged from ~10kcal/kg lean body mass (LBM) in the group who had been assigned to the lowest amount of Ensure, a liquid food product that was the only food source the subjects received during the treatment period to ~40kcal/kg lean body mass in the group with the highest intakes.

Table 1: Thyroid hormone concentrations before treatment and changes in concentrations resulting from 4 days of controlled energy availability | Tq, thyroxine; fT4, free T,; T3, triiodothyronine; rT3, reverse T3; ff3, free T3 (Loucks. 1999)

As you can see in Table 1 the thyroid hormone concentration in the two lower groups (10kcal and 19kcal/kg lbm) dropped significantly. With a 10% decrease in free T3 only the changes in the 10.8kcal /kg lbm group were physiologically significant.

Bottom line: In a previous experiment (12), the scientists had been able to show that energy availability, rather than dietary energy intake or exercise energy expenditure separately, is the behavioral factor affecting thyroid regulation in exercising women. It is thus not exactly surprising that 4 days on an energy deficient diet in the study at hand were enough to induce a low T3 syndrome in the female participants of the study at hand.

Figure 3: Mean T3 thyroid hormone levels after 20 days of total fasting, 800kcal diet without carbohydrates and 800kcal diet consisting almost exclusively of carbs (Spaulding. 1976)

In this context it's important to point out that the effect occured only, when the dietary inake fell below 50% of the dietary requirement and that the changes in thyroid hormone levels are restricted to T3 and won't show up on tests that evaluate TSH and T4, only.

In studies of the effects of dietary restriction on thyroid metabolism in sedentary obese patients, T3 levels declined only when dietary energy intake fell below a particular threshold and the carbohydrate con- tent of the diet influenced the location of this threshold. T3 levels fell when energy intake was reduced to 800 kcal/day if carbohydrate content was <200kcal/day. Previous studies also highlight that a reduction of carbohydrate intake, will reduce the amount of free T3 by increasing the conversion of T4 to the inactive thyroid metabolite rT3.

Irrespective of the fact that a high(er) carbohydrate diet can help women maintain normal thyroid function on a diet, studies indicate that there is an energy threshold below the amounts of carbs in the diet become irrelevant and the T3 levels crash as a simple consequence of a lack of energy in the diet (Spaulding. 1976) | Comment on Facebook!

References:

• Loucks, Anne B., and Edward M. Heath. "Induction of low-T~ 3 syndrome in exercising women occurs at a threshold of energy availability." American Journal of Physiology 266 (1994): R817-R817. 
• Spaulding, Stephen W., et al. "Effect of caloric restriction and dietary composition on serum T3 and reverse T3 in man." The Journal of Clinical Endocrinology & Metabolism 42.1 (1976): 197-200.