Weight Gain: Protection Against Hyperthyroidism?

It’s been said that if an elephant’s metabolic rate were the same as that of a mouse, the elephant would spontaneously combust. This would happen because, although an elephant burns many more calories in total than does a mouse, a mouse burns many more calories per unit mass than does an elephant.  Burning calories leads to heat production. But because an elephant cannot dissipate heat nearly as easily as a mouse can, an elephant with a mouse’s metabolism would become so hot internally that, theoretically anyway, the animal would burst into flames.

Now, keep our unfortunate elephant in mind when reading the following statement: “If you eat 5,000 calories of only fat and protein, some protein will be converted by gluconeogenesis, some will go to building muscle, the fat will go to building hormones and cellular repair and the rest will be converted to heat by various metabolic processes and wasted.”

Like me, I’m sure you’ve read some version of the above belief a few times before – that is, the idea that all excess calories from fat and protein are dispelled from the body as heat when one is on a low carbohydrate diet. But as you can see from the theoretical elephant, creating heat is not always a good thing. Heat generated internally will raise core body temperature unless it is dissipated via the body’s surface area into the external surroundings. Maintenance of core temperature is something the body must regulate within a very narrow range by some combination of thermogenesis (heat creation) and heat dissipation/conservation. Too little heat generated and/or conserved will cause hypothermia and too much heat generated and/or conserved will cause hyperthermia. Both conditions can be fatal. Because animals have a limited body surface area from which to release heat, they cannot produce heat in an unrestrained manner without risking hyperthermia. These facts should call into question the assertion that all excess calories consumed on a low carb diet will be converted to heat and wasted. Note that I said all excess calories; it has been shown experimentally that humans can increase their energy expenditure (which creates heat) when overfed 1,000 calories a day so that many individuals will not gain as much weight as expected. The most “genetically lucky” individuals were able to increase their metabolisms to such an extent as to dissipate 600 of the extra 1,000 calories. So yes, some calories can be wasted as heat, but we must remember that thermogenesis does not occur in a haphazard manner and so we cannot assume that an unlimited amount of calories can be spent in heat production without some negative consequence arising.

Jules Hirsch and Theodore Van Itallie were thinking along these lines in 1973 when they penned a letter to the editor in The American Journal of Clinical Nutrition. They were critiquing a study done by Heinrich Kasper that purported to show that a normal weight adult individual (it’s not clear if the subject was male or female) gained no weight over a 10 day period of consuming 5,950 calories per day with most of the calories (4,988) coming from fat (corn oil). Kasper and colleagues conjectured that the lack of weight gain could be evidence of “luxus consumption” (heat creation as a means of wasting energy so that it will not be stored as fat) but when Hirsch and Van Itallie crunched the numbers, they showed just how potentially metabolically damaging disposing of 2,900 calories a day could be:

“If one were to accept the authors’ contention that “ . . .under a relatively low carbohydrate and protein intake, increasing amounts of fat produce an increase in the metabolic rate that becomes particularly marked if fats high in linoleic acid are given,” then the reader appears to be drawn into the following chain of calculations. A young man requires approximately 3,000 kcal/day, assuming a modest activity level. Approximately one-half of this amount is needed to support his basal metabolism (BMR). If, by consuming large quantities of corn oil, he then increases heat production sufficient to dispose of 2,900 (5,900 minus 3,000) additional calories, this “luxus consumption” would seem to require an elevation of the subject’s BMR by nearly 200% (on the average). Because patients with severe hyperthyroidism exhibit a BMR somewhat in excess of +50%, the data of Kasper et al. would call for this normal young subject to manifest a degree of hypermetabolism (24 hr/day) three- to fourfold greater than that associated with the most toxic form of Graves’ disease. It is perhaps not out of place to mention also that, for every degree (Fahrenheit) of temperature rise above normal, there is supposed to be an associated 8% increase in metabolic rate. In view of this fact, it seems inconceivable that the sensation of “heat over the entire body” reported by the subjects on a high corn oil intake could account for the almost 200% increase in BMR implied by the observations of Kasper et al.”

Using Hirsch’s and Van Itallie’s reasoning, let’s crunch the numbers on the subjects in the overfeeding study who were able to dispose of 600 extra calories per day. Since the subjects in this study were said to be sedentary (as opposed to modestly active), let’s bump their caloric requirement down to 2,500 calories/day. Assuming that about one-half of the total caloric requirement is needed to support basal metabolism, the subjects’ BMR would be approximately 1,250 calories/day. Wasting 600 calories per day would require an increase in BMR of a little less than 50%. Confounding the calculations is the fact that the subjects in the overfeeding experiment were gaining weight where as the subject in the Kasper study was not, but it’s interesting to speculate if a 50% elevation in BMR is the maximum increase the body will allow when trying to dispose of excess calories. Thyroid hormone is the primary regulator of thermogenesis; if the body wants to burn off excess calories, it must produce and release more thyroid hormone.  Too much thyroid hormone can have deleterious effects on health including coma and death.  According to Hirsch and Van Itallie, problems with severe hyperthyroidism begin when one's BMR increases above 50% of normal.  It appears some (lucky?) individuals can rev up their metabolisms to that point before they start storing fat.  Most of us however cannot and maybe that's not such a bad thing after all.

Glycero and Gluco Neogenesis: Related but Not Twins

I recently became aware of a blog posting by Dr. James Carlson that was inspired by my article Is the Fable of Unfettered Fat Burning Derailing Your Low Carb Diet?.  Dr. Carlson was asked by a Facebook follower to read the article and to elaborate on the "mechanism where your body can accumulate or at least not lose fat because of dietary protein intake".  I'm assuming the mechanism she is referring to is the biochemical pathway glyceroneogenesis which can use amino acids from dietary protein to synthesize the glycerol backbone necessary for triglyceride formation.  You can read Dr. Carlson's response here.  Although I may be mistaken, it seems Dr. Carlson is stating that glyceroneogenesis is simply gluconeogenesis with an additional step at the end.  Because that is not what glyceroneogenesis is and because my article was the impetus for the discussion, I feel the need to clarify.

Most people who follow low carb diets know what gluconeogenesis is: the creation of glucose from non-carbohydrate sources like lactate, glycerol, and glucogenic amino acids. Certain cells in the human body can only utilize glucose for fuel and gluconeogenesis is the process the body uses to make glucose when very little carbohydrate is coming in via one's diet. Gluconeogenesis takes place primarily in the liver and the resulting glucose is released into the bloodstream where it travels to the cells that need it. Again, I could be wrong, but it appears Dr. Carlson is stating that glyceroneogenesis  =  gluconeogenesis in the liver  +  glycerol 3-phosphate formation via glycolysis in fat cells. In other words, he believes glyceroneogenesis occurs when glucose formed in the liver from lactate, glycerol, or amino acids is taken up by fat cells and transformed into glycerol 3-phosphate, the glycerol backbone of a triglyceride molecule. Theoretically, this could happen but this process is not glyceroneogenesis. Glyceroneogenesis occurs in the fat cells themselves - no liver required. Glucogenic amino acids (or lactate) are taken up directly by fat cells and transformed into glycerol 3-phosphate by what would best be described as a truncated version of gluconeogenesis:

Although both (gluconeogenesis + glycolysis) and glyceroneogenesis can potentially provide the glycerol 3-phosphate necessary for triglyceride synthesis (aka body fat accumulation) on a low carb diet, I find glyceroneogenesis the more compelling candidate.  In general, only the amount of glucose needed for those cells that require it will be produced by gluconeogenesis.  And that requirement is not very much - I've seen references for as little as 40 grams of glucose per day during prolonged fasting or very low carb intake.  This glucose is consumed only by those cells that need it so that there is no "extra" for fat cells to use to make glycerol 3-phosphate.  Also, glycerol 3-phosphate synthesis from glucose occurs via glycolysis, and glycolysis is greatly reduced in fat cells during low carb intake.  Unlike glycolysis, glyceroneogenesis is up-regulated in fat cells during low carb intake.  The only major barrier to glyceroneogenesis when insulin is low is lack of substrate, but since many low carb dieters eat a good amount of protein, this scenario won't necessarily happen without conscious intervention.

Does this mean that reducing dietary protein is a good strategy for encouraging fat loss on a reduced carbohydrate diet?  In my opinion, it could work, but should only be attempted if fat loss has stalled for an appreciable amount of time or if one is gaining body fat.  Reducing protein intake is tricky - it has the potential to cause a loss of muscle mass which is something most of us don't want.  A good idea would be to calculate your individual protein need to see where you stand.  If you find that you are eating more protein than you need and you are not experiencing much in the way of fat loss success on a low carb diet, try reducing your protein intake a bit (or maybe more than a bit depending on how much you're eating).  Your body may be a pro-glyceroneogenesis machine and delivering less amino acid substrate to your fat cells may just do the trick.

Note:  the biochemical pathway diagrams in this article are technically correct but not complete.  In other words, I hope they help you understand the article but if you want to pass a biochemistry exam, don't study these diagrams or you will surely fail!  ;)

Is the Fable of Unfettered Fat Burning Derailing Your Low Carb Diet?

According to many low carb diet advocates, “carbohydrate drives insulin drives fat storage” is an elegantly uncomplicated yet scientifically unassailable summation of the diet’s weight loss rationale. To become lean, they assert, simply stop eating carbs in any appreciable amount; consuming carbohydrate prompts the pancreas to release the hormone insulin, and insulin is the primary promoter of body fat storage. No carbohydrate ingestion, no insulin response, no fat storage, end of story. There is no need to limit the amount of protein and fat you eat because they do not stimulate much of an insulin response (this is especially true of fat). So, as long as you forfeit sugary and starchy food, you will lose body fat and be immune to body fat gain regardless how much protein and fat you consume. To strengthen their assertion, low carb diet proponents often offer the following four points as proof that insulin, via carbohydrate ingestion, is the key physiological factor promoting body fat storage:


1) Insulin traps fat inside fat cells by down-regulating the action of Hormone-Sensitive Lipase (HSL), an enzyme that catalyzes the breakdown of triglycerides (the storage form of fat) into fatty acids. Whereas triglycerides cannot leave fat cells because they are too large, the smaller fatty acids can. They escape into the circulation and are now available to be “burned” to supply energy to other cells in the body. Because high blood sugar caused by carbohydrate intake elevates insulin, HSL will be switched off after a carb-rich meal, triglycerides will not be broken down into fatty acids, and fat will remain trapped in the fat cells. The opposite occurs during low insulin states such as fasting and low carb dieting: HSL action will not be inhibited, triglycerides will be broken down, and the resulting fatty acids will be free to leave the fat cells to be burned for energy.

2) Elevated insulin and blood sugar from carbohydrate ingestion are necessary for fat cells to make the molecule glycerol 3-phosphate. Glycerol 3-phosphate is an essential component of triglyceride synthesis. If fat cells cannot synthesize triglycerides, they cannot store fat. A more detailed explanation of this argument can be found here.

3) Carbohydrate intake causes a considerable increase in insulin that is not counteracted by a concurrent increase in glucagon, a pancreatic hormone that stimulates fat cells to release fat. Compared to carb intake, protein intake causes a much smaller increase in insulin as well as an increase in glucagon; this means that eating protein assists in burning body fat.

4) Untreated Type 1 diabetics, who produce essentially no insulin, cannot keep fat in their fat cells and consequently become emaciated. This phenomenon proves that insulin is the primary promoter of body fat storage and cannot be supplanted by any other physiological factor.

No doubt, the scientific arguments are very compelling, but are they accurate? Personal accounts abound on the internet of people stating that their low carb diets are yielding less than stellar results. Stalling after an initial loss of body fat, failing to lose much fat at all, or even gaining fat from the start have all been reported. If the low carb science is absolutely correct and if the diet is being followed properly, these experiences should be virtually impossible. So, that raises the question: are the low carb failures lying or are the low carb proponents wrong? Let’s take a more in-depth look at body fat metabolism and in particular the four points mentioned above, and then you can decide for yourself.


Point #1: Carbohydrate Consumption leads to Elevated Insulin leads to HSL Suppression leads to Trapped Fat.
Very true – elevated insulin, via carbohydrate intake, does indeed trap fat inside fat cells by suppressing the action of HSL. But that’s not the only mechanism the body has for entrapping fat. Take, for example, two studies done in the late 1990’s that showed that ingestion of a low carb/high fat meal or infusion of a pure fat load directly into the bloodstream resulted in almost no fat being released from fat cells (1, 2). The researchers, surprised by their results, stated “Intracellular lipolysis (the breakdown of triglycerides into fatty acids within fat cells) …was suppressed almost completely with both oral and intravenous fat load. Insulin is a major regulator of HSL activity, yet this showed only a slight increase after the oral lipid load and a gradual decrease during and after the intravenous load. It seems that suppression of HSL activity can occur without insulin.” The researchers also stated that their results “may reflect a novel mechanism for the regulation of fat storage.” A major contributor to this mechanism is certainly Acylation Stimulating Protein (ASP). ASP is a hormone made by fat cells primarily in response to consuming fat, and it does quite a nice job of trapping fat in fat cells without the aid of insulin (3).

Point #2: Glycerol 3-phosphate (G3P) synthesis is dependent upon carbohydrate intake, high insulin, and elevated blood sugar (glucose).
No, it isn’t. During prolonged fasting in humans, up to 40% of the fatty acids released from fat cells are taken up again and converted back into triglycerides in fat tissue (4). Triglyceride synthesis requires G3P. During fasting, fat cells cannot use glucose to produce G3P since glycolysis (the breaking down of glucose) is minimal in this state. Another source of G3P must be available. This is where a biological pathway called glyceroneogenesis comes into play. Glyceroneogenesis utilizes non-glucose substrates such as amino acids and lactate to synthesize G3P. The key glyceroneogenic enzyme, PEPCK-C, is up-regulated during fasting when both insulin and glucose are low (5). Because low insulin and low glucose are also consequences of low carb dieting, it’s not much of a jump to suggest that PEPCK-C will be up-regulated then as well. This can drive the production of G3P from amino acids supplied by dietary protein which in turn can allow the production of triglycerides from fatty acids supplied by dietary fat.

A few low carb proponents have acknowledged the existence of glyceroneogenesis, but state that it occurs at a rate not even worth mentioning. Apparently, they took what is known regarding the rate of glyceroneogenesis during the “normal” condition of mixed dietary intake and assumed that glyceroneogenesis is merely a minor metabolic pathway that doesn’t do much of anything under any condition, never considering that low carb dieting can (and does) change the equation.

#3: Protein Consumption leads to Elevated Glucagon leads to Fat Burning.
When I was in college some 20 years ago, my biochemistry text listed the hormone glucagon as one of a number of hormones having a major stimulatory effect on lipolysis. Perusing a more recent textbook however will reveal that glucagon has been dethroned. Glucagon’s association with lipolysis was just that – an association. Think about what occurs during fasting: insulin is low, glucagon is high, and a lot of fat is being liberated from fat cells and burned for energy. But that doesn’t necessarily mean that glucagon is causing the lipolysis; it may just be going along for the ride. In other words, correlation does not equal causation. When tested directly, it was found that glucagon in fact does not stimulate lipolysis in fat tissue (6, 7). Glucagon’s primary function is to maintain blood sugar levels by stimulating the liver to either release its stored glucose or to make glucose from substrates such as amino acids or glycerol. Why would protein consumption cause a rise in glucagon when carbohydrate and fat consumption do not? Dietary protein stimulates the pancreas to release insulin, sometimes to an even greater extent than carbohydrate (8). Because insulin decreases blood sugar, glucagon must be released at the same time to prevent blood sugar from getting too low.

All this being said, it's important to point out that eating protein can aid in fat loss and beneficial body composition changes in several ways unrelated to glucagon.  Of the three macronutrients, protein has the highest thermogenic (calorie-expending) effect.  And as I'm sure you know, not eating enough protein can have deleterious effects on muscle mass.


Point #4: Insulin is the primary regulator of body fat storage as evidenced by untreated type 1 diabetics.
Individuals who produce no insulin and do not receive it exogenously have an extremely difficult time storing body fat regardless of what or how much they eat. This is an undisputed fact. As mentioned earlier, ASP is a hormone that stimulates triglyceride synthesis and effectively traps fat in fat cells in an insulin-independent manner. If type 1 diabetics produce ASP in response to fat ingestion (and there’s no reason to think that they don’t), why can’t they store dietary fat after a mixed meal in spite of their lack of insulin? The answer can be found by looking at insulin’s effects on carbohydrate metabolism and the liver, not its direct effects on triglyceride synthesis and fat tissue. Insulin prompts the liver to synthesize glycogen from blood glucose and store it. The liver’s ability to store glycogen is critical because the body needs to have a readily available source of glucose to remedy any potential hypoglycemic episode: when blood sugar gets too low, glucagon causes the conversion of liver glycogen to glucose which is then released into the circulation. In the state of total insulin depletion however, the liver cannot store glycogen although it’s physiologically compelled to do so. In a futile attempt to fill the liver’s glycogen stores, muscle and fat tissue are catabolized to provide amino acids (from muscle protein) and glycerol (from fat cell triglyceride stores) as substrates for glycogen synthesis. The body is going to the extreme measure of wasting its muscle and fat tissue because maintaining stable blood glucose is exceedingly important to the brain’s functioning – and a liver with a well-maintained glycogen store is the body’s best defense against a hypoglycemic crisis. This demonstrates that total insulin deficiency causes extreme metabolic derangement. The wasting of muscle tissue and body fat to make glycogen in a desperate attempt to ward off low blood sugar during a time when blood sugar is abundant may not make sense, but the body is doing what it thinks is best – it’s just that the lack of insulin prevents it from having all the information it needs to make an informed decision, so to speak.

Like the liver, skeletal muscle requires the presence of insulin to store glycogen (10). Muscle glycogen is important because it supplies the muscles with the energy they need to perform anaerobically (lifting something heavy, sprinting away from an attacker, etc). If, after glycogen-depleting exercise, an individual fails to eat, his muscles will use amino acids from stored body protein as substrates for glycogen resynthesis (11). In other words, the muscles will consume some part of themselves until they are satisfactorily filled with glycogen. Now let's take this a step farther and consider what would happen to skeletal muscle under the condition of total insulin depletion: the muscles would have a very difficult time storing glycogen because the breaking down of glycogen (glycogenolysis) is essentially unrestrained. Because the glycogen stores are not filling up, muscle protein will continue to be catabolized to provide amino acids. Triglycerides in fat cells will also be catabolized to provide glycerol for glycogen synthesis. So, just as the liver will seek out any and all substrates to fill its glycogen stores when insulin is absent, skeletal muscles will do the same.


So, it appears that for untreated type 1 diabetics, insulin is indeed the primary regulator of body fat storage. ASP can synthesize and store fat as much as it's able; under the condition of complete insulin deficiency, the body will just steal it away from fat cells to get the precious glycerol it contains. But how does all this relate to insulin-producing people? Insulin, even in low amounts, allows the liver and muscles to store glycogen albeit in smaller amounts than when insulin is high. This moderate amount of glycogen is enough to prevent the massive fat (and muscle) tissue catabolism seen in type 1 diabetes. It also explains why ASP, without any insulin present, can cause fat cells in test tubes to make and store triglycerides, but why it can’t do the same in the human body: test tubes do not have livers and skeletal muscles desperately seeking large amounts of glycerol, but a human body lacking insulin does. The ability to produce insulin takes these glycerol-hungry tissues out of the equation, making both insulin and ASP potentially equally powerful promoters of body fat storage.  The extent to which insulin or ASP promotes body fat storage in an individual is largely genetically determined.


There are few things more frustrating than following a diet philosophy to a T yet failing to achieve the body fat reduction promised by the diet's promoters. If you experienced disappointing results while on a low carb diet, it's not because you are a physiological freak, it's because the mantra "carbohydrate drives insulin drives fat storage" is entirely too simplistic. The human body has the means to synthesize and store body fat when insulin is low. And if you follow a low carb diet yet fail to create a calorie deficit (9) that's exactly what it will do. For some individuals, low carb dieting offers an effortless method for achieving a calorie deficit mainly by appetite suppression. Others, however, must consciously restrict the number of calories they consume. The great thing about reduced carbohydrate diets (when compared to high carbohydrate diets) is that even while consciously limiting calories, people rarely get ravenously hungry. Periods of mild hunger are tolerable and in the grand scheme of things can be considered a part of the natural human condition (surely our Paleolithic ancestors experienced a growling stomach periodically). Although the notion of intentional calorie restriction is anathema to some low carb diet proponents because they firmly believe in the unfettered fat burning capability of a low insulin state, the physiology presented above clearly shows why some people have to consciously restrict the amount of food they eat. We are fortunate to live in a society where food is abundant and easy to obtain. Some of us have more of a "drive to eat" than others. Because our modern way of life doesn't force us to limit calories, we sometimes have to do it ourselves.


References
1) - Effects of an oral and intravenous fat load on adipose tissue and forearm lipid metabolism.
Evans K, Clark ML, Frayn KN.
Am J Physiol. 1999 Feb;276(2 Pt 1):E241-8.

2) - Peripheral fat metabolism during infusion of an exogenous triacylglycerol emulsion.
Samra JS, Giles SL, Summers LK, Evans RD, Arner P, Humphreys SM, Clark ML, Frayn KN.
Int J Obes Relat Metab Disord. 1998 Aug;22(8):806-12.

3) - Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation-stimulating protein and insulin.
Van Harmelen V, Reynisdottir S, Cianflone K, Degerman E, Hoffstedt J, Nilsell K, Sniderman A, Arner P.
J Biol Chem. 1999 Jun 25;274(26):18243-51.

4) - Glyceroneogenesis and the triglyceride/fatty acid cycle.
Reshef L, Olswang Y, Cassuto H, Blum B, Croniger CM, Kalhan SC, Tilghman SM, Hanson RW.
J Biol Chem. 2003 Aug 15;278(33):30413-6.

5) - Fatty acid recycling in adipocytes: a role for glyceroneogenesis and phosphoenolpyruvate carboxykinase.
Forest C, Tordjman J, Glorian M, Duplus E, Chauvet G, Quette J, Beale EG, Antoine B.
Biochem Soc Trans. 2003 Dec;31(Pt 6):1125-9.

6) - Action of glucagon and glucagon-like peptide-1-(7-36) amide on lipolysis in human subcutaneous adipose tissue and skeletal muscle in vivo.
Bertin E, Arner P, Bolinder J, Hagström-Toft E.
J Clin Endocrinol Metab. 2001 Mar;86(3):1229-34.

7) - Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis.
Gravholt CH, Møller N, Jensen MD, Christiansen JS, Schmitz O.
J Clin Endocrinol Metab. 2001 May;86(5):2085-9.

8) - An insulin index of foods: the insulin demand generated by 1000-kJ portions of common foods.
Holt SH, Miller JC, Petocz P.
Am J Clin Nutr. 1997 Nov;66(5):1264-76.

9) - The Energy Balance Equation by Lyle McDonald
If you are one of those people who doesn't believe that it's necessary to create a caloric deficit in order to lose weight, this article will set you straight.

10) - Skeletal muscle glycogenolysis is more sensitive to insulin than is glucose transport/phosphorylation. Relation to the insulin-mediated inhibition of hepatic glucose production. Rossetti L, Hu M.
J Clin Invest. 1993 Dec;92(6):2963-74

11) - POST-EXERCISE MUSCLE GLYCOGEN REPLETION IN THE
EXTREME: EFFECT OF FOOD ABSENCE AND ACTIVE
RECOVERY.
Paul A. Fournier, Timothy J. Fairchild, Luis D. Ferreira and Lambert Bräu
Journal of Sports Science and Medicine (2004) 3, 139-146

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