Tuesday, September 29, 2009

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.

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


Paul A. Fournier, Timothy J. Fairchild, Luis D. Ferreira and Lambert Bräu
Journal of Sports Science and Medicine (2004) 3, 139-146



OhYeahBabe said...

Just stopped by to say thanks for commenting on my blog. Great post here - I'm going to have to read it again to make sure I understood it. Thanks for including detailed references! I hope you decide to write more!

LynMarie Daye said...

Hi OYB! I keep thinking that I need to revise that blog post to make it more understandable but the subject matter is rather complicated and if reading it twice is necessary for it to be understood, then maybe that's just the way it has to be ;`).

I do plan on writing more. My next post will probably be about dieting beliefs becoming like religious beliefs. My thoughts are inspired by your recent posts and by a small passage I read recently in the book "Rethinking Thin" by Gina Kolata. It will undoubtedly be shorter than my previous post and without scientific references
because it's just some thoughts I have on the matter. I'm going on vacation soon, so it will probably have to wait for a bit.

Thanks for stopping by and keep up the good work!

Nigel Kinbrum BSc(Hons)Eng said...

Hi LynMarie.
Someone's just referred me to this post. Would you like to "join the fray" at I have a theory?

LynMarie Daye said...

Hi Nige,

I would love to join the fray but there doesn't appear to be much fraying going on. ;`P

It's nice to be able to discuss this topic (that some people have to consciously restrict food intake on a LCHF diet) in a civil manner. After Taubes' book came out, it seems you couldn't do that. Any discussion would degrade into name-calling and such. It's nice to see that that has changed and that differing theories with scientific support are given consideration and not just tossed aside as "it conflicts with Taubes so it can't be true". That kind of thinking is rarely good; you only have to look at current government dietary recommendations to see that (Ancel Keys anyone?)

What brought you here is the metabolic pathway glyceroneogenesis. It's a rather unknown pathway although it was elucidated years ago. I did a search on Google books and the only text it was mentioned in was a veterinary book. That was a few years ago so maybe that's changed. I never heard of it until I went looking for it. I put all kinds of search phrases into PubMed and finally struck gold after several days. I felt like I won the lottery! :`P This was before Taubes' book came out. What prompted my search was a posting made by a PhD in Biochemistry on the Protein Power forum. He was explaining why it was essentially impossible to gain body fat while on a LC diet because of the lack of alpha-glycerol phosphate. My personal experience told me this was not true, but his argument seemed solid. After I discovered glyceroneogenesis, I didn't go back to the PP forum to discuss it. Little ole me with my undergrad degree in Biology versus a PhD? I guess I'm a wimp!

An interesting note on Taubes: he does know about glyceroneogenesis. He mentions it briefly during a lecture that you can find online. Maybe I'm imagining things, but he seems to do so begrudgingly. I'll try to find that lecture if you're interested.

I'm glad you found my article. If you have any comments, questions, or criticisms, fire away. I certainly don't know everything and will not be offended if you find holes in my arguments.

Nigel Kinbrum BSc(Hons)Eng said...

Hi again LynMarie.

I've Emailed Taubes about my theory but I won't hold my breath waiting for a reply!

I've also aired my theory on Don’t You Wish You Were As Smart as Lyle McDonald? and Can protein turn into fat?

I have one of Taubes' lectures linked in my Blog. Is glyceroneogenesis mentioned in that one or do I have to watch it again? :-/

I'm a retired Electronic Engineer so I suspect that people don't think much of my theory on those grounds. Mind you, Richard K Bernstein was also an Engineer and he's done rather well in the field of Diabetes.


P.S. I've enabled Email follow-up, so I'll notice any replies here sooner.

LynMarie Daye said...


This is the lecture I was referring to: http://video.google.com/videoplay?docid=4362041487661765149#

Glyceroneogenesis is mentioned at 59:30 minutes.

Here is another lecture where the word glyceroneogenesis is shown on a slide, but it is not actually mentioned: http://webcast.berkeley.edu/event_details.php?webcastid=21216

Look 47:25 minutes into the lecture.

Nigel Kinbrum BSc(Hons)Eng said...


I heard glyceroneogenesis mentioned in the first lecture, but I didn't see it in the 2nd at 47:25. At 1:12:35, I saw "A small quantity (of alpha glycerol phosphate) is made during gluconeogenesis". In the first lecture, the substrate for glyceroneogenesis was said to be Amino Acids (AAs).

If someone was to drink just oil or eat just butter, would there be sufficient AAs available to produce sufficient glycerol?


LynMarie Daye said...

Oops! The lecture with the glyceroneogenesis reference at 47:25 is -
Dartmouth lecture

"If someone was to drink just oil or eat just butter, would there be sufficient AAs available to produce sufficient glycerol?"

Since oil and butter are basically 100% fat, then no, there would not be sufficient amino acids to produce glycerol via glyceroneogenesis if we only consider the butter or oil itself. Of course, we have amino acids available from muscle tissue that could theoretically be used. Reference # 11 in the blog article discusses the body's willingness during fasting to convert amino acids from muscle into glycogen to replenish muscle glycogen stores depleted by heavy exercise. So the body isn't averse to "wasting" muscle protein if it deems it necessary. However, we as a species very rarely came into contact with food that was 100% fat. Butter and oils are modern foods. Our fat and proteins came packaged together for many, many thousands of years, so I wouldn't be suprised if we don't possess a mechanism to store dietary fat without either protein or carbs. I hope that made sense! :`)

Nigel Kinbrum BSc(Hons)Eng said...


I linked Taubes' name to the Dartmouth lecture. I've watched it more than once but missed the subtle display of glyceroneogenesis.

The fattiest natural food that we would eat would probably be salmon heads (if we weren't so fussy!). I gather that Bears eat loads of those to fatten themselves up for hibernation.

If we swallow too much fat on its own, it gets ejected by reverse peristalsis. If it fails to be fully absorbed during digestion (Xenical/Alli anyone?), it re-appears at the far end as "the soily oilies". Either way, it's nasty!


Marnee said...

Uh I thought the point of Taubes book was that carbohydrate consumption, and the insulin fat storing mechanisms, are what lead to obesity and serious metabolic and other diseases, not that it simply makes you gain weight. Only people who don't know little about the hormonal regulatory system would insist that insulin is all there is to it.

I think ASP is a highly unlikely cause of significant weight gain or weight loss stalling, unless one is very much overeating past the point of satiety AND is exercising too much (both of which stimulate ASP). As such, ASP is unlikely to cause significant weight gain.

I am surprised that the thyroid is
not mentioned anywhere in here.

According to wikipedia:

The thyroid controls how quickly the body uses energy, makes proteins, and controls how sensitive the body should be to other hormones.

It is easy enough to imagine that a SAD diet coupled with way too many halides ingested over time could lead to deranged thyroid function and therefore poorer weight regulation and even weight gain even without any other significant hypo or hyper thryoid symptoms?

Anonymous said...

What an excellent post.

Join our discussion over on livinlavidalowcarb forum! Your blog posting started it all.

Personally, I can't lose weight eating all the full fat cheese, butter and fatty meat that I want. I need to keep the carbs AND calories down.

Thanks for a great post.

LynMarie Daye said...

Sorry Anonymous it took me so long to post your comment; I had to travel away from home for work.

I read the thread at Jimmy Moore's forum. He commented that he would like to interview an expert on ASP. I'd suggest Dr. Katherine Cianflone. She and her colleagues were the first to discover ASP and she has spent much of her working life studying it. If she would consent to an interview, I have no way of knowing. She is not a diet book author or coach like most of Jimmy's podcast guests and she may not be into translating her work into "laypeople speak" if you know what I mean. But then again, may be she'd love to. You don't know unless you ask. :~)

As for contact info - her email address is easy to find, but I don't want to display it on a public blog. I would suggest going to pubmed.gov, putting "cianflone k" into the search area at the top and selecting one of her research papers. Contact info for the authors is usually printed on the first page.

Anonymous said...

does length of triglyceride eatten effect ability to store it as claimed by the Coconut oil folk?

LynMarie Daye said...

I don't know as much about MCT's as I'd like to, but I believe it's pretty much an accepted fact that they aren't incorporated into chylomicrons like long-chain fatty acids are (therefore no ASP response). They travel directly to the liver from the intestines so they have a greater chance of being used for energy as opposed to being stored in fat cells. In fact, MCT's are sometimes used as a fat source in ketogenic diets for epileptic children because it's believed they cause a higher degree of ketosis than LCT's. This allows the children to have a more liberal diet in terms of protein and carbs yet still stay in ketosis.

I've heard of people supplementing their diets with coconut oil (as in eating it by the spoonful) because they believe it has a thermogenic effect. AFAIK, the thermogenic effect has never been shown to be very substantial. I think a better idea would be to replace some of the fat in the diet with coconut oil. MCT's have also been shown to reduce appetite a bit. All in all, I believe coconut oil can aid in weight loss, but it's not a magic bullet. As far as I'm aware, there is nothing preventing medium-chain fatty acids from being incorporated into very low density lipoproteins (VLDL) in the liver if they escape becoming ketones. This gives fat cells a second chance at storing them. If anyone has evidence to the contrary, please let us know.

Anonymous said...
This comment has been removed by a blog administrator.
LynMarie Daye said...
This comment has been removed by the author.
LynMarie Daye said...

I'm sorry! To the person who posted a question, I accidentally deleted your post. Please send it again if you wish and I promise to be more careful!

Anonymous said...


I have a question for the webmaster/admin here at adipo-insights.blogspot.com.

Can I use some of the information from this blog post above if I give a backlink back to this website?


LynMarie Daye said...

Fine by me :)