Will NuSI clear the bar?

Gary Taubes is out with a new article in Scientific American ... rehashing the same old same old, and essentially getting paid to write a press release for NuSI.  

What Makes You Fat: Too Many Calories, or the Wrong Carbohydrates?

Rigorously controlled studies may soon give us a definitive answer about what causes obesity—excessive calories or the wrong carbohydrates

We get the rehashing of how WWII stopped Bergmann and Bauer's Lipophilia Hypothesis from becoming the working hypothesis for obesity, and yet another primer on calories vs. carbohydrates.  We again are asked to ignore the obvious -- that Americans are definitely eating more, on average, with no concurrent need for those calories, and likely moving a bit less as well.   The obesity epidemic that supposedly was instigated by the low fat craze is blamed on the fact that much of our additional caloric load is in the form of carbohydrates.  This is not supported by one of Gary Taubes' own paradoxical cultures, the Pima, who did not eat a low carb diet prior to the 1900's, let alone billions of humans all over the globe.   Or .... despite the "modern paleo's" insistence, the paleolithic diet in the literature -- both cited for the basis of the diet and that used in clinical trials.  

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Exercise & Fat Mobilization ... and starving cells & hunger

There's no denying it, TWICHOO is down to a broken toothpick where the science is concerned.  (See here for the toothpick reference if you're a newer reader.)   The remaining claim supporting TWICHOO rests on the action of insulin on the fat cell.  Insulin does indeed act to stimulate esterification and suppress lipolysis, favoring deposition and accumulation of triglycerides in fat cells.  They even teach this stuff in some medical schools I'm told!  So these days it's all about how carbs make you hungry and overeat (although overeating is so inane) because they stimulate insulin which traps all your fat calories in your fat starving the rest of your cells of energy.  Now, that part's not true, but let's for the sake of argument assume it is.  What, then, would cause you to lose weight and not be hungry?  Why anything that favors net mobilization of fat stores -- that is stimulates lipolysis and fatty acid release from fat cells.  This will raise the circulating free fatty acid, NEFA, levels and make them available in abundance to your cells.  Hunger be gone!  It's all about the balance of the TAG/FFA cycle.

Well, if that is the case, then exercise would be THE most effective means of preventing or reversing fat accumulation.  Hands down.  No argument.  Oh ... and it wouldn't make you hungry, quite the opposite, because your body is awash in fatty acids.  Work with me here TWICHOOB's.  If you have your hypothesis, you must fit it or apply it to all situations.  Exercise is the ultimate TWICHOOB miracle weight loss dream.   Because if anything that works to put fat into fat cells is fattening, then anything that works to get fat out of fat cells is de-fattening.

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Glyceroneogenesis & The Triglyceride/Fatty Acid Cycle Revisited

Glyceroneogenesis and the Triglyceride/Fatty Acid Cycle   (TAG/FA)

JBC Papers in Press, June 4, 2003, DOI 10.1074/jbc.R300017200

Lea Reshef, Yael Olswang, Hanoch Cassuto, Barak Blum, Colleen M. Croniger, Satish C. Kalhan, Shirley M. Tilghman , and Richard W. Hanson

The above paper is referenced in Good Calories, Bad Calories, and is a paper I believe one cannot read thoroughly and still believe that dietary carbohydrate is required in order to "fix" fat and become obese.  It has been quite a while since I read it in its entirety.  Doing so in recent days I've noticed even more information in this paper that counters the whole notion that more dietary carb leads to more glycerol-3-phosphate leads to more esterification of fatty acids to the storage triglyceride form.   More specifically, these four paragraphs/excerpts were somewhat drowned out for me in my first reading:

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Why Insulin Levels & Lipolysis Do NOT Dictate Weight Loss ~ Part I

I'm really rather amazed that at this point we're still having to discuss this topic.  As a good friend of mine once said to me in an email (paraphrasing):  One would expect these sorts of myths to persist back in the 80's and 90's.  But in this day and age of information availability on the internet, it seems impossible that enough people continue to be influenced by such easily debunked notions.  Low carb Wiener anyone? {grin}

In any case, it seems that no amount of demonstrating the lack of any correlation between fasting insulin levels and weight loss will convince some people.  I really would think that the scatterplot (weight loss v. fasting insulin), discussed in this post,  would be impossible to explain away, and yet many just dismissed it from their minds.  It's that proverbial black swan all the Eades Popperites (or is that all you can eat (Eade)sous vide popper-bites?) constantly seek.  

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Flashback! Da Bomb that started it all

Anthony Colpo, bless his carb-loaded heart, linked recently to the first post of mine that went *semi* viral.

Glyceroneogenesis v. Taubes

I thought I'd bump that up for those who have just stumbled upon my little neck of the low carb webwoods.  Also, the original link to the lecture no longer is active.  But it is on Youtube and I'll post the links below:

Gary Taubes Dartmouth Lecture Part 1 of 7
Part 2 of 7
Part 3 of 7
Part 4 of 7
Part 5 of 7
Part 6 of 7
Part 7 of 7

Oh, listening to this lecture again .... sooooooooo much more material there....

Just two:

• Pima ate beans and wheat and corn!  Oh my!
• We need to lock people up in metabolic wards and see what happens when they eat this nutrient or that nutrient.  Oh, double my!  

Love you all my dear readers :D

Ketogenic Diet increases Fat Mass and Fat:Total Body Mass Ratio

Ketogenic diet-fed rats have increased fat mass and phosphoenolpyruvate carboxykinase activity

This study looked at body weight, fat mass, blood lipid and glucose levels and PEPCK (rate limiting enzyme in glyceroneogenesis pathway for G3P production for esterification of fatty acids - fat deposition) activity in the liver and fat cells.  Two ad libitum diets were compared, a control standard chow and a ketogenic zero carb chow.  This study was in normal, young (30 days old at start) Wistar rats and lasted 6 weeks.

The diet compositions are shown below:

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Non-esterified fatty acid metabolism and postprandial lipaemia

Non-esterified fatty acid metabolism and postprandial lipaemia

Yet another gem from ... who else? ... Keith Frayn!

Non-esterified fatty acids (NEFA, or free fatty acids) are an important metabolic fuel. Both the concentration of NEFA and their flux through the circulation vary widely from hour to hour, reflecting nutritional state and physical activity. Inappropriately elevated plasma NEFA concentrations may have a number of adverse effects on both carbohydrate and lipid metabolism.

As my regular readers know well, this is a focus of my research.

These adverse effects are likely to be most marked in the postprandial period, when NEFA release from adipose tissue is usually suppressed. Although the regulation of NEFA release in the postabsorptive state is well understood in molecular terms, the predominant pathway for release of NEFA in the postprandial state is the action of lipoprotein lipase (LPL) in adipose tissue capillaries on chylomicron-triacylglycerol (TG). Fatty acids released by LPL may either be sequestered in the adipocytes by esterification, or released as NEFA into the plasma. The regulation of this branch-point, which may be of crucial significance for postprandial metabolism, is not well understood. Factors stimulating tissue retention of fatty acids include insulin and acylation stimulating protein.

1998 Keith Frayn

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Oh Nevermind ..... (Taubes and G3P)

Poor Gary Taubes is embarrassed by his whole glycerol phosphate debacle, and since that was just too difficult a subject for dummy laypersons to understand anyway, he just left it out of his upcoming book.  So let's just forget about that one folks and move on.  He takes the opportunity to set the record straight in an interview, had time to post two long blog posts rehashing his latest spin on carbs and such, but hasn't addressed this issue in print despite at least one commenter asking about it.  He "hopes" to be able to get to such heady topics at some future point.  I'm not holding my breath!

But I think Mr. Taubes should have his feet held to the fire on this issue and not be allowed to get away with a simple "oh nevermind" on a key aspect of his theories.

One can listen to his latest (James Kreiger bashing **more on this at the end of this post) interview HERE.  It's a bit of a tough listen with audio difficulties and such, but the issue I want to address comes around the 51:30 mark where he addresses his "bone headed" mistakes in GCBC.  

Listen to that and now go back and listen to his mea culpa at around the 41:30 mark in his interview with Jimmy Moore HERE.

Some inconsistencies jumped out at me right away:

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GCBC Reference Check ~ Part III of ? ~ Is glycerol phosphate rate-limiting?

In his most recent interview with Jimmy Moore, Gary Taubes did a bit of a mea culpa on the notion that dietary carbs are required to store fat.   He offers up a rather weak description of how he got it wrong for so long in his lectures ("skewed") and claims this wasn't something from the book but rather the lectures. Originally my post here stated that strictly speaking this was true, but upon rereading those sections of GCBC it is quite obviously not.  One could even go so far as to say it is the lynchpin of his hypothesis, but that is open to interpretation.  Still, Taubes repeated in the interview that G3P is "rate limiting" in the esterification process, a claim he made unequivocally  in GCBC.  Here's the relevant paragraph:

A single molecule plays the pivotal role in the system.  It goes by a number of names, the simplest being glycerol phosphate.  This glycerol-phosphate molecule is produced from glucose when it is used for fuel in the fat cells and the liver, and it, too, can be burned as fuel in the cells.  But glycerol phosphate is also an essential component of the process that binds three fatty acids into a triglyceride.  It provides the glycerol molecule that links the fatty acids together. †116  In other words, a product of carbohydrate metabolism -- i.e., burning glucose for fuel -- is an essential component in the regulation of fat metabolism: storing fat in the fat tissue.  In fact, the rate at which fatty acids are assembled into triglycerides, and so the rate at which fat accumulates in the fat tissue, depend primarily on the availability of glycerol phosphate.  The more glucose that is transported into the fat cells and used to generate energy, the more glycerol phosphate will be produced.  And the more glycerol phosphate produced, the more fatty acids will be assembled into triglycerides.  Thus, anything that works to transport more glucose into the fat cells -- insulin, for example, or rising blood sugar -- will lead to the conversion of more fatty acids into triglycerides, and the storage of more calories as fat.

In his footnotes, Taubes cites the following book:  Regulation in Metabolism by Newsholme & Start, 1973.  Here are two of the citations because I think their wording would indicate that Taubes feels this text is authoritative, and, presumably if he's recommending it, he has read it himself. 

An excellent review of the regulation of fat metabolism and adipose tissue is Newsholme and Start 1973:  195-246.

Glycerol phosphate:  For a review of the role of this molecule, the triglyceride/fatty-acid cycle, and the glucose/fatty acid cycle, see Newsholme and Start 1973:214-34.

OK, so I did go "see" for myself.  I've been somewhat sitting on this one for a while because I think it is particularly damning given specific wording of the excerpts from this text I'm about to share.   I wanted to share it first in my interview with Jimmy (even though that won't air for a few months).

What I transcribe below is the section in Chapter 5 Adipose Tissue and Fat Metabolism entitled "The control of esterification" that deals with this theory:  {} are my comments ;-)

In the case of the hypothetical, primitive animal it has been shown how large changes in blood glucose concentration could automatically cause reciprocal changes in plasma fatty acid concentration.  However, in the rat the blood glucose concentration does not fall by more than 30% during two days of starvation and this would appear to be insufficient to cause the marked increase in fatty acid mobilization that occurs under these conditions.  During the same period the plasma insulin level is decreased by about 80% (ref 41, see Table 7.3) and this hormone is known to regulate esterification.  Insulin stimulates the membrane transport of glucose into the adipose tissue cell and increases the rate of glycolysis and the glycerol phosphate concentration.  During starvation the reduction in the plasma insulin level results in a decreased rate of glycolysis and a lowering of the glycerol phosphate concentration.  This restricts esterification and consequently fatty acid mobilization is stimulated.   {I know what you're thinking ... so far so good right?} 

This theory is supported by the fact that the content of glycerol phosphate in adipose tissue is decreased during starvation and it is markedly increased when adipose tissue from a starved animal is incubated with glucose and insulin.  {Here is where I believe, having heard all he needed to hear, Taubes stopped reading ... but read on dear readers}   There are a number of problems associated with the simple idea that esterification is controlled by the membrane transport of glucose.  First, there is no evidence that the concentration of glycerol phosphate is limiting for the process of esterification (the Km for glycerol phosphate of the first enzyme in the pathway is not known).  Second, since glycerol phosphate dehydrogenase catalyses a reaction which is close to equilibrium, the concentration of glycerol phosphate can be controlled by both the cytoplasmic [NAD+]/[NADH] ratio and the concentration of dihydroxyacetone phosphate. (ref 42)

Dihydroxyacetone phosphate + NADH ↔ Glycerol phosphate + NAD+   

These quantities may vary independently of the glycolytic rate. (ref 17)  Third, the addition of adrenaline, fatty acids or acetate to the incubated fat pad preparation stimulates esterification but does not increase the content of glycerol phosphate. (ref 42)  This experiment suggests that factors other than the glycerol phosphate concentration can regulate esterification.  Such factors remain unidentified at present.  Nonetheless, it must be emphasized that a marked decrease in the concentration of glycerol phosphate could limit the rate of esterification and therefore variations in its concentration must always remain a potential mechanism of control.

The entire first paragraph essentially lays out a hypothesis, and evidence consistent with that hypothesis is included in the opening sentence of the second.  But the gist of the remainder of this paragraph is to lay out the case AGAINST it.

I don't know how much more bluntly Newsholme and Start could have stated the first point.  To repeat:  

"there is no evidence that the concentration of glycerol phosphate is limiting for the process of esterification."

Just how does one go from that to:

In fact, the rate at which fatty acids are assembled into triglycerides, and so the rate at which fat accumulates in the fat tissue, depend primarily on the availability of glycerol phosphate.

???????????????????   You'll note I'm picking at Taubes' wording here too.  He uses that word fact, not probably, not "could", not that this is some conjecture etc.

The second point is really the biggie here.  Let me try to explain this to those without a degree in chemistry.  All chemical reactions can theoretically proceed in either direction, so that if A + B → C + D, then C + D → A + B.  Many chemical reactions are considered irreversible because one direction is much more energetically favorable than the other.  The energy requirement to go in reverse is simply too high.  Combustion of hydrocarbons is a good example (e.g. burning propane).  But other reactions can go in both directions, we call these reversible reactions, and use the double arrow to indicate this (actually it's usually two arrows in opposite directions on top of each other, often with the length of the arrows reflecting the preferred direction).     If we put compounds A&B, C&D, or three or all four of them into a beaker, initially one reaction occurs at a faster rate but both are occurring until the system reaches a state of equilibrium.  At equilibrium, the concentrations of A, B, C, and D remain constant, and we can define an equilibrium constant (Keq) that represents a ratio of these concentrations.  This makes the system appear static, but it is actually a dynamic equilibrium with the rates of the forward and reverse reactions being equal.  There is a principle called LeChatelier's Principle that applies to systems in equilibrium.  In short, if we do anything to displace the system from its equilibrium state (in chemistry we usually referred to this as perturbing the equilibrium or applying a stress), the reaction rates will temporarily "shift" in order to re-establish the equilibrium.  One way we can do this is to add one or more of the compounds to the system.  The equilibrium constant Keq is called a constant for just that reason.  If I add more A to the system above that is at equilibrium, I have increased the concentration of A and thus altered K (which is a ratio of the concentrations).  The system will react so as to lessen the concentration of A so as to bring K back to Keq.  This would involve a "shift to the right" being an increase in the reaction rate of the forward reaction.  (If you're interested in the math involved, here's one example).

So what they are saying in the second point is that the

DHAP + NADH ↔ GP + NAD⁺ 

reaction is close to equilibrium and therefore should behave in the manner described above.  If we add DHAP then GP formation should increase.  If there's more NADH, it should as well, and if there's more NAD⁺ then the reverse reaction should "consume" GP and reduce its concentration.  But the concentrations of these other three components of the equilibrium system vary in ways that are not correlated with how much glycolysis is going on.  Were this system controlled simply by LeChatelier's Principle, then increases in DHAP (an intermediary in glycolysis) would exert predictable changes in the other three components of this system.  Rather, the conversion of DHAP to GP is determined by the activity of an enzyme.

On to point 3 that directly addresses whether it is the G3P level (however manipulated) that is rate limiting in esterification.  The addition of adrenaline, fatty acids OR acetate alone can increase esterification rate without a corresponding increase in the G3P level in the cell.   Of course at the time of publication, the text states that the mechanisms of this were not yet known.  I suspect ASP is working it's magic here.  The lack of change in G3P level indicates two possibilities, either basal G3P levels are in sufficient excess of needs that whatever stimulates esterification only depletes the G3P slightly as it is incorporated into triglycerides, or fatty acid uptake (or adrenaline or acetate) stimulates G3P production to meet the needs to esterify FA's but the additional G3P is consumed in the esterification process so that the level remains unchanged, or both.

Bottom line:  This reference DIRECTLY contradicts that which Taubes cites in GCBC and implies is discussed in this text.  At a minimum, Taubes should have done what he says he does  and follow the research forward to present day.  That there were factors unknown in 1973 should have led him to further research and no doubt to discover ASP.  But he clearly didn't want to.  

Throughout this process, I necessarily made judgments about the quality of the research and about the researchers themselves.  I tried to do so using what I consider the fundamental requirement of good science:  a relentless honesty in describing precisely what was done in any particular work, and a similar honesty in interpreting the results without distorting them to reflect preconceived opinions or personal preferences […]  I hope that I, too, will be judged by the same standard.    

~ Gary Taubes in Good Calories, Bad Calories

Just doing my part here.  Taubes' continued silence on these matters "speaks volumes".

---

If this comment remains here, it means that to date that you are reading this post, Gary Taubes has not formally addressed this very real criticism and issue with his writings.  He has also failed to set the record straight in any meaningful forum which is why you still have people claiming, to this day, that you can't store fat or get fat without dietary carbohydrate.

Glyceroneogenesis Is the Dominant Pathway for Triglyceride Glycerol Synthesis in Vivo in the Rat

Glyceroneogenesis Is the Dominant Pathway for Triglyceride Glycerol Synthesis in Vivo in the Rat*

OK ... yes, this is a rat study, but the body of work by Hanson's group has demonstrated that the results obtained for the rat correlate well with human metabolism.  These studies utilized radiolabeling "tracer" methods to track the substrate source for G3P.  Three dietary groups were compared:

1.  Controls - regular chow fed (removed 7am study morning)

2.  48 hour fasted (food removed 48 hrs prior)

3.  Lipogenic (high sucrose) diet (5 day sucrose water in addition to regular chow and glucose infusion during testing to "maintain the lipogenic state").

The abstract is long so I'll let y'all readers just read it at the source if you like.  I'll focus this post on excerpts from the discussion of the results.

Plasma:  The plasma concentration of triglyceride were not different in the three groups (Table 1). The fraction of plasma triglyceride glycerol derived from glyceroneogenesis was ∼60% and not different among the three groups (Table 1). Approximately 15% of triglyceride glycerol was derived from glucose in the control group (Table 1). The contribution of glucose was lower in 48-h fasted rats (∼11%) and was higher in sucrose-supplemented animals (∼28%). Although sucrose supplementation resulted in a higher contribution of glucose to plasma triglyceride glycerol when compared with controls, the contribution of glucose was less than that of glyceroneogenesis (Table 1).

The highlighted  statements say it all.  No difference in triglycerides or the fraction of those triglycerides formed using glyceroneogenesis-derived G3P between the groups.

Glyceroneogenesis and Glycolysis as G3P source in Adipose Tissue:  There was no significant (p = ns) difference in the triglyceride concentration in the adipose tissue of controls and 48-h-fasted animals. In the sucrose-supplemented animals, the concentration of triglyceride was significantly higher than controls (Table 2).

FAT ACCUMULATION OCCURRED IN THE SUCROSE-SUPPLEMENTED RATS ONLY.  CARBY CHOW-FED RATS DID NOT ACCUMULATE FAT 

Note:  It is important to remember that one way human and rat metabolisms differ considerably is in the rate of de novo lipogenesis (aka converting excess carbs to fat) and it's contribution to fat stores - that being that DNL is not a major pathway in humans for fat storage (see my DNL label for some posts on this) but is in rats.  It is also important to note the use of the word "supplemented":  e.g. the sucrose rats were getting an excess.  

This section continues:

... The rate of glyceroneogenesis in the control animals was ∼600 nmol/g/h in the epididymal adipose depot and ∼800 nmol/g/h in the mesenteric depot (Table 2). Glyceroneogenesis did not change in response to fasting for 48 h. In contrast, sucrose-supplementation resulted in a significant increase in this pathway in both adipose tissue depots. Glyceroneogenesis was higher in mesenteric adipose tissue as compared with epididymal adipose tissue in all groups; however, a statistically significant difference was only observed in the sucrose-supplemented group (Table 2).

... 48-h fast caused a significantly lower incorporation of total glucose carbon into triglyceride glycerol as compared with controls. In contrast, sucrose supplementation resulted in a higher total contribution of glucose carbon to triglyceride glycerol (Table 2). The direct contribution of glucose to triglyceride glycerol was ∼80 nmol/g/h in control animals in both adipose depots (Table 2). In the 48-h-fasted animals the direct contribution of glucose via glycolysis was negligible. In contrast, sucrose supplementation resulted in a doubling of the direct contribution of glucose to triglyceride glycerol in both adipose tissue depots.

We confirmed the predominance of glyceroneogenesis, as compared with glycolysis,.... We examined the mesenteric adipose tissue of sucrose supplemented rats because glyceroneogenesis was highest in the adipose tissue of this group. ... [the results show] ... a greater contribution of glyceroneogenesis relative to the direct contribution of glucose via glycolysis to triglyceride glycerol synthesis (Fig. 3). 

Fatty Acid Synthesis in Adipose Tissue:  The incorporation of 14C of glucose into fatty acids was negligible in 48-h-fasted animals and high in controls in both the epididymal and mesenteric adipose tissue (Table 4). Furthermore, fatty acid synthesis in the sucrose-supplemented group was significantly higher as compared with control animals in both adipose tissue depots examined.

Note: epididymal and mesenteric adipose depots are types of visceral fat.  Interesting, no?  Glyceroneogenesis rates in the fat generally considered to be the more metabolically active are not changed by fasting vs. normal feeding.  They increase in response to sucrose supplementation.  So excess carbs caused an increase in G3P production from pyruvate/lactate.  So much for the view of GlyNG as a minor alternative path.  Sucrose did increase the absolute contribution from glycolysis, but the contribution of GlyNG was also stimulated.  Again, it should be remembered that DNL is a more significant pathway for triglycerides in the rat.  So those rats made fatty acids from the excess glucose, used some of the glucose to make G3P, but made the additional required to esterify the synthesized fatty acids predominantly from GlyNG.   

My take-away message from this discussion is that the body gets the G3P it needs to esterify the fat it needs to store from the available substrates.   Since humans use less glucose for DNL than rats, it is possible we use more to make G3P when it is "lying around", but GlyNG occurs at considerable rates continually, and is at the ready to "step up" when needed.  The body has better uses for glucose apparently under normal conditions, and it has a ready supply of other substrates to make G3P in adipose tissue.

Glyceroneogenesis in the Skeletal Muscle: Our data are the first demonstration of glyceroneogenesis in skeletal muscles. In response to fasting as well as sucrose feeding, glyceroneogenesis was the main contributor to triglyceride glycerol formation, whereas the direct contribution of glucose was not measurable. .... Although we anticipated that glyceroneogenesis would be a functional pathway, due to the presence of PEPCK-C activity in skeletal muscle (14), the dominance of this pathway was unexpected. Even more surprising was the lack of a direct contribution of glucose to G-3-P synthesis, given that in response to a glucose load, skeletal muscle is responsible for the majority (∼85%) of insulin-mediated glucose uptake (62). Our data demonstrating a marginal contribution of glucose to triglyceride glycerol in skeletal muscle are consistent with the report of Guo and Jensen (15)...

Hepatic (Liver) Glyceroneogenesis:  The fractional contribution of gluconeogenesis to the glucose Ra changed as expected (about 30% lower in controls, which increased to ∼60% after a 48-h fast), whereas glyceroneogenesis remained constant at about ∼60% under all conditions studied. Furthermore, glyceroneogenesis, and not glucose metabolism via glycolysis, was the dominant pathway for hepatic triglyceride glycerol synthesis, even in sucrose-fed, glucose-infused animals. ...

The above are pretty self-explanatory.

I saved the opening paragraph of the discussion for last, as it summarizes the above nicely:

In the present study we have examined the relative contribution of glyceroneogenesis and glucose via glycolysis to triglyceride glycerol synthesis in the rat. Our data show that glyceroneogenesis is quantitatively the predominant pathway for triglyceride glycerol synthesis in white adipose tissue, skeletal muscle, and liver during extended fasting as well as during periods of glucose availability. Surprisingly, the highest rates of glyceroneogenesis in adipose tissue were observed in sucrose-supplemented animals, when fatty acid synthesis and triglyceride deposition were high.

The *surprising* high rates of glyceroneogenesis under lipogenic conditions - e.g. conditions under which the rats were making fatty acids - are consistent with what is expected to go on in a low-carb, high-fat fed state.  Only now the source of fatty acids is directly from the diet ("deposited" by chylos).  There is no reason to believe that GlyNG wouldn't be increased in response to the *need* to store those fatty acids.   

In conclusion the authors outline where the understanding of GlyNG regulation remains unresolved.

(Note:  I'll address the epinepherine part at some future date)

Last, but not least, I would be remiss if I didn't address the date and source of this paper.   It was submitted in June of 2008 and first published in July 2008.   This was after the initial release of GCBC, but Hanson (a co-author) has been identified by Taubes as having vetted his version of G3P in the book to ensure its accuracy.  GCBC was released relatively late in 2007 (September).  This current article was rather detailed and embodied a considerable amount of research.  Given the amount of work that would have gone into writing up the material, it is reasonable to assume that the research itself was mostly complete if not concluded months prior - e.g. though not compiled, no researcher ignores the results as they record data!  Most of the work may well have been completed in advance of Hanson's review of GCBC.   In other words, it seems unlikely that Hanson's view on the role of G3P and glyceroneogenesis was altered considerably from before the publication of GCBC to after as Taubes implies.  That the latest work wasn't published formally until 2008 is not evidence of some great sea change in the understanding of the role of GlyNG in esterification.  There's no evidence that this work did anything more than strengthen the mounting evidence of GlyNG's importance as a metabolic pathway (as summarized in the 2002 & 2003 papers).  I'm still left most befuddled by this aspect of the controversy.  At the very least, I think it was incumbent upon Taubes to follow this up instead of  repeating his G3P theory in lecture after lecture as if it were established fact.

Update: Gary Taubes, Email & My Response

I was recently invited by Jimmy Moore to appear on his podcast in response to some of my recent posts on Gary Taubes' most recent lecture and his interview with Jimmy.  This elicited the following email to me from Gary Taubes.  (Aside:  My email is open to anyone who wishes to use it through my profile here).  At his request, I have included it in its entirety here along with my responses.  Taubes' words are in default font, my responses are in green italics.

************************************************

Hi Carb Sane,
   I hope you don't mind me taking the liberty of e-mailing you. Jimmy Moore told me that you might be going on his show,  which prompted me to try to read a few of your latest blog entries. Occasionally, friends have suggested I read and respond to your critiques (attacks?) , but whenever I try I find them tough going. Your descriptions of what I wrote or said or argued never quite seem to mesh with what I actually wrote or said or argued and your certainty that you are right and that I'm a dishonest sleazeball have made me hesitant to spend time and effort trying to convince you otherwise.

No problem emailing me.  It is better than hearing from you second hand through Fred Hahn for example.  Can you provide me with one example of where I have mischaracterized what you wrote or said??  As to my opinions of you and your motivations they have developed over time reading and listening to you.  Whether or not you feel compelled to convince me otherwise is up to you.  I'm just another blogger on the internet after all.  Critique v. attack is a fine line.  When I discover something that is intellectually dishonest (as I find your omission of glyceroneogenesis in GCBC to be, for example), I'll call it as I see it.   

   In this case, though, you asked me a simple question, to "name names", as you put it, once again implying that even on such a simple subject as this I'm bullshitting the innocent public. So, the "biggest expert in the country" (I hope I didn't phrase it like that, but doing a radio show is a different business than writing, so if I did... sigh) was indeed Richard Hanson. If you look in the acknowledgements of GC,BC you'll see Hanson among those thanked for reading the book and critiquing it in draft. You can e-mail him and ask him, if you'd like, although when I contacted him in March after my NIH lecture, he said he was dealing with cancer and would get back to me shortly. He didn't, and I didn't push it for the obvious reason.

Thank you for naming names.  It seemed odd to me that you so frequently (one could say almost universally) do so in your book and lectures that it came across as odd that you would not do so with the young biophysicist(s) on at least two occasions, and now Hanson.   FWIW, the way you phrased your assessment of Hanson was spot on in my view, we agree!  I just have a hard time believing he would tell you that, circa 2007, your section on G3P was accurate.  

 The two young NIH biophysicists were Kevin Hall and Carson Chow. You can pull up Kevin's papers by searching "Hall kd adipose" in Pubmed. The English guy who agreed with Hall and Chow's take was Keith Frayn at Oxford.

Thanks again for these.  I must say that my suspicions on the "English guy" were wrong.  Hence my thinking of why you might not wish to name him at this point.  Still, you now say you were corrected in 2008.  Why did it take until the most recent lecture to leave out what you knew was obviously wrong from the lectures, and to finally admit you got it wrong in your interview with Jimmy?  Your excuse that you don't have a blog or a platform doesn't pass the smell test.  You've "taken questions" and responded to Dr. Eades' readership before, I've seen him share communications from you on his blog, as have others (e.g. Josef Brandenberg).  If I used a default template I could have had my blog up and running here in 5 minutes, and you know for sure that you would have a hundred followers in a matter of hours.  I'll be looking into Hall and Chow's research to see if it warrants a conclusion that the G3P issue doesn't matter because insulin is such a controlling factor in it all.

  Feel free to ask any further questions. As I suggested to James Krieger in an e-mail exchange a few months ago I'm all for critical assessments of the evidence and my interpretations. And I make this point in the epilogue of GC,BC. It's absolutely necessary. Science doesn't function without it and I wish the establishment would care as much as you do about shooting me down. (Far more pleasing than being ignored, although ideally they would do more intellectually honest job of it than you do.)

Excuse me?  Where have I demonstrated dishonesty - intellectual or otherwise?  I have addressed problems with your theories with evidence.  Where did I go wrong in my analysis of Shai for example?  If it seems like I and others care a lot about "shooting you down" it is because you have a large and loyal following that deserves to know the truth, not separated from more of their money in a desperate search for answers.  To that end I don't think you should be instructing medical professionals in theories when you have neither the background nor the qualifications to do so (again, my opinion).  If you aren't going to volunteer to correct your errors, others will have to raise the noise level.  I see nothing wrong with this.  Actually, in the interest of science, don't you think those of us possessing evidence counter to your theories are obligated to share that?  So again, why the two year lag?  Can you see where that lag alone, aside from the facts, doesn't cast you in a good light?  It seems only when enough evidence was posted demonstrating that not only were you wrong, but you should have known that you were prior to the publication of GCBC, did you finally decide to speak out.

If I can help you criticize my work, and do a better job, I'm happy to help. I just ask that you do a better job of describing correctly what I actually wrote and said and argued.

Again, please provide details specifics of where I have described what you wrote or said inaccurately.  

As it is you're getting a failing grade and the glass house you're living in when you write your critiques seems awfully fragile.

Oh ... was I being graded?  Who is grading me?  LOL.   Please show me the graded exam Sir.  Which critiques are on fragile ground?  SPECIFICALLY.

 Also the ad hominem shit is beneath you and doesn't help your case any. You seem compelled to attack me  for what you perceive as dishonesty and venality (taube$) when scholarly incompetence, time-pressure, stress and the limitations of one admittedly fallible individual would be far more reasonable explanations.

Ooooh ad hominem!  She made an ad hominem!!  Sheesh.  This is a familiar pattern I've seen with others in your circle of friends.  Just saying is all.  I won't waste time distracting from the facts by addressing my occasional speckling of posts with my opinions and speculations on your motivations, etc.  

Since I have your ear, perhaps you can specifically address the issue I raised in Glyceroneogenesis v. Taubes.  That being how you could have still written what you did in light of the fact that the 2003 Reshef paper (Hanson coauthor) was among the references in GCBC, and the content thus known to you well in advance of publication.  

Frankly, I consider financial interests to be a relatively understandable explanation for your behavior relative to your other proposed alternatives.  After all, you have to make a buck right?  Kids, as you mentioned a few times in your latest interview, to put through college.  It is forgivable that you let GCBC go to print with known errors because you had a large advance that was no doubt spent doing all of your research.  The same goes with honest mistakes that may or may not have been compounded by stress and time constraints.  But to not correct the record in the intervening years?

  

Would you REALLY prefer I charge you with scholarly incompetence?  Actually that would be an explanation had you not hit on at least a few references that already refute many of your theories.   But if you claim this as a defense, what on Earth are you doing lecturing (educating) others?

Your work would be more compelling and would certainly be taken more seriously if you left your presumption of motive -- something you can know nothing about -- out of it.

Perhaps.  I'll let my readers decide.  Seems I'm taken rather seriously just being me.  I think my readers are smart enough in their own right to know that I'm venting/speculating my opinions.  They're free to draw their own conclusions.  Again, is there some explanation for the Reshef/G3P contradiction I'm missing?

It’s as though you’re dedicated here not just to proving that you’re smarter than I am, but that you’re morally superior as well. The first ambition is diminished greatly by the second. You say you fear cyberstalkers in your life, and yet you come across like someone who has devoting their life to stalking me.

....

....

....

Sorry, I'm back now.  I think I have the laughter under control.  Is your ego really that out of control that you are accusing me of devoting my life to stalking you?  Do you have a clue just how silly that sounds?  As of receipt of your email my blog contained 169 posts only 11 of which were tagged GCBC fact check, and a handful specifically addressing your work directly.  (That total count doesn't even include probably at least half that many additional posts lying in my draft bin waiting for finishing touches while I tend to what sparks my interest on a particular day).  I did really start my blog (and continue to post regularly on everything from fatty acid contents of foods to in depth analyses of studies to posting links and abstracts for future reference) to organize and share my research.  Since I'm interested in getting the science right, you've been on my radar screen as a prominent voice who has gotten a lot wrong.  I don't care if anyone thinks you're smarter or I'm smarter or what.  That's just childish.  As for moral superiority?  I make no claims there either.  But I'm sure not the first blogger on the web to express an opinion or to speculate on dishonest behavior when I see it.  

As to my concerns re: cyberstalking these are specific to the nature of personal issues I've shared.  I'm already concerned that you seem to be aware of this concern using that particular term, as I've only ever used it in my emails with Jimmy (re: our upcoming podcast interview).  I don't think Jimmy intended to betray a confidence, but this kind of thing can happen too easily for my comfort.  Frankly, I don't really care if folks on the internet know everything about me so much as I do not want real life acquaintances to know as much about me as I've shared on the personal blog.  I think most of my readers would understand that or at least have no interest in wasting time on malicously pursuing me.  I still share the information in hopes that it might help others who see a bit of me in themselves ... in the hopes that my journy out of binds I've been freed from gives hope that others can gain freedom too.  But, on the internet you never know if there's someone out there with malicious intent, so I maintain anonymity for my own protection.  If anyone reading this feels I'm somehow less credible for it, let them judge for themselves and find another blog to read, perhaps.  There could be no reason other than malice to attempt to "out" me.  It certainly would add nothing of substance to the discussion.  In the end, I'm not selling anyone anything.  I write on a free blog site and nobody needs ever read a word I write.  I could weigh 100 or 800 lbs and eat Pritikin or drink 4L of Coke a day or survive on coconut milk and jerky, and it still doesn't change the serious inconsistencies I've uncovered in your work.   Your work being published for profit and referenced ubiquitously in the LC community as a "definitive" work.   If you're going to present yourself as an expert, you should be prepared to answer to critical reviews of your work.  I'm all ears if/when someone finds an error in my research or interpretations of data.  THAT will lead to constructive discourse.  Not crying "ad hominem" any time someone criticizes your work on the basis of the evidence.  And certainly not accusing your detractors of stalking!  I'm not following you around the country heckling you at lectures or delving into your personal life.  Even if my blog were All GCBC Critique All the Time, that still wouldn't be stalking any more than the various websites that exist solely to pay homage to your book are.  

   Reporting the facts or the strict nature of the disagreement between us would suffice and would actually benefit both your readers and mine. Disagreeing with my interpretation of the facts and the evidence I marshal to support my argument is perfectly valid.

My writing style is what it is.  I think the bulk of my work is reflective of evidence-based arguments.

I might even learn something from your work (although from what I've read so far, I doubt it.)

Just a thought:  When offering advice to others on their writing style, it behooves one to refrain from doing that which they're accusing others of.  If scholarly ineptitude is really your defense, I might suggest you start by reading the various posts I've made under the Insulin Resistance tag so as to correct that flawed theory in your book as well.  Please do report back when you haven't learned a thing.  

Assuming that you know what I was thinking while I wrote and that my motives are less pure than yours, other than from what I  might have stated explicitly in the book, is not necessary and will be counter productive should any serious reader try to follow your arguments.

Again, I'll let my readers decide for themselves the value of the information I present and whether or not sharing my opinion alters its value.  I don't presume to know what you think, I am speculating based on the evidence available to me.   The 2003 reference to Glyceroneogenesis in your book doesn't add up.  And there is more to come as I have discovered some inconsistencies with other references that are even more glaring.  

   I hope this helps.
  All the best,
  Gary Taubes

PS. If you want to post this e-mail, feel free. I just ask that you post the whole thing and not part of it. If you want to keep it private, that's fine with me. I'm CC-ing Jimmy Moore, since it was Jimmy who spurred me to try once again to read your posts.

I think both of you could benefit from reading more of them.

***********************************************

Quick Edit to Add the brief note I sent with the full email:

I've replied with my point by point responses in italics.  I will gladly share your responses in their entirety on my blog, or you can respond in the comments to the post where I've shared this email:  http://carbsanity.blogspot.com/2010/10/update-gary-taubes-email-my-response.html

I do look forward to hearing back from you and hope you will address the issues I've raised.

Regards

Of Thermodynamics, Chemistry, Biology and Biochemistry

The detractors of energy balance theory often say something along the lines that thermodynamics goes out the window in living organisms, the rules don't apply.  Nope.  The existence of the Second Law does not violate the First Law!

This simply isn't true, and those who say similar must simply not understand these fields.  Humans are not bomb calorimeters or Carnot cycle/combustion engines.  When Dr. Eades tried to discredit Anthony Colpo a while back, he and his compadre Feinman waxed poetic and evoked nightmares of steam tables in their college thermo courses.

Read more »

ASP activates Glucose transport in Human Adipocytes

ASP stimulates glucose transport in cultured human adipocytes  (Full Text PDF)

Introduction

Acylation Stimulating Protein (ASP) is the most potent stimulant of triglyceride synthesis in human adipocytes yet described.1 The rate at which triglycerides are cleared from the plasma appears to be related not only to the functional activity of LPL but also to the capacity of peripheral tissues to store fatty acid as intracellular triglycerides. The ability of ASP to regulate this process may, therefore, be of physiological importance.2,3 As human adipocytes differentiate, they become competent to synthesize and secrete the three proteins necessary to generate ASP. These are the third component of complement (C3), factor B, and adipsin.4 The capacity to produce ASP appears relatively late in differentiation but before the sharp increase in the capacity of adipocytes to synthesize triglyceride.5 Subsequently, the mass of triglycerides within adipocytes, the rate at which they synthesize triglycerides, and their capacity to generate ASP are closely correlated.4,5 Moreover, as they differentiate, not only do human adipocytes generate more ASP,  they become much more responsive to ASP.4 

The mechanisms by which ASP increases triglyceride synthesis are under intensive study. Interaction with an apparent membrane receptor appears to be critical6 and studies of the cell signalling mechanism point to activation of a protein kinase C pathway.7  ASP increases triglyceride synthesis by two coordinate mechanisms. One is to increase the activity of diacylglycerol acyltransferase, the enzyme which controls the last step in the synthesis of a triglyceride molecule.8 The other is to increase specific membrane transport of glucose through specific effects on translocation of glucose transporters. This second effect of ASP has only been demonstrated in human skin fibroblasts and recently in L6 myotubes.9,10 The purpose of the present study was to determine if ASP produced this effect in human adipocytes, a physiologically important tissue in glucose homeostasis, and to compare its potency to that of insulin.

Discussion

The data from the present study demonstrates: 

(1) that ASP stimulates specific membrane transport of glucose in human preadipocytes and adipocytes in a time and concentration dependent manner

(2) that differentiated adipocytes are more responsive to ASP than preadipocytes

(3) that ASP is as potent as insulin in inducing specific membrane transport of glucose in adipocytes.

These data extend our knowledge as to the mechanisms by which ASP causes triglyceride synthesis to increase in human adipocytes. Our previous work focused primarily on triglyceride synthesis.   Experimental data demonstrated that both omental and subcutaneous adipose tissue (primary adipocytes or cultured adipocytes) are responsive to ASP13,14  although the stimulation is greater in subcutaneous tissue suggesting regional specificity.13

The physiological significance of these effects is becoming increasingly apparent. Until recently, triglyceride clearance from plasma was thought to be determined exclusively by lipoprotein lipase activity, greater triglyceridehydrolytic capacity resulting in more rapid removal of triglyceride from plasma.15,16  However, the correlation between lipoprotein lipase activity and triglyceride clearance is poor17,18 and studies have shown that, in fact, lipoprotein lipase would appear to be present in excess.15 There is direct evidence in humans that the rate of fatty acid uptake from triglyceride-rich particles is limited.19 A major portion of the fatty acids released from chylomicrons are not immediately taken up by adipocytes20 but rather continue to circulate. Thus, the rate of chylomicron triglyceride hydrolysis by lipoprotein lipase is not a direct function of the mass of this enzyme present on the endothelial surface, but the increase in ambient circulating fatty acids can also result in product inhibition of lipoprotein lipase and influence triglyceride clearance.19,21±23

Our hypothesis has been that adipocyte triglyceride synthesis determines the rate at which fatty acids are taken up by adipocytes from the adjacent capillary space. This rate will influence the proportion of fatty acids which enter adipocytes directly after lipolysis as opposed to the proportion which exit the adipocyte capillary space and pass within the circulation to the liver. A decreased rate of adipocyte fatty acid uptake results in increased delivery of fatty acids to the liver and subsequently, increased VLDL production.24 Any factor which increases the rate of fatty acid uptake and triglyceride synthesis will enhance the efficiency of adipocyte triglyceride storage. Normal plasma ASP in a group of healthy control subjects (35±65) is 32.0 2.6 nM.25 Plasma ASP increases postprandially 26 up to two-fold and is a potent in vitro stimulator of triglyceride synthesis in human adipocytes4 and may thus enhance adipose tissue efficiency.

However, fatty acids are not the only building block required for triglyceride synthesis and storage. Glucose is the source of the glycerol-3-phosphate backbone, and it is well known that glucose transport increases postprandially in response to hormone stimuli.27,28 The present study adds importantly to the documentation of this pathway in humans. That ASP causes specific membrane transport of glucose to increase in adipocytes is clear, although we have not in this instance directly demonstrated the mechanism responsible for this effect.  Based on our previous results in cultured human skin fibroblasts and L6 myotubes, ASP likely induces translocation of glucose transporters.9,10 In the fibroblast model, ASP induced translocation of glut-1 transporters to the cell membrane whereas in the L6 myotube model, ASP stimulates translocation of glut-1, glut-3 and glut-4 transporters, all to the same extent as insulin. As well, the fact that lower ASP concentrations are more effective at increasing glucose transport in the differentiated adipocytes is consistent with our previous observation that the effects of ASP on triglyceride synthesis become more pronounced during the process of adipocyte differentiation.4 Although higher concentrations of ASP were necessary to achieve the same stimulation as insulin, it should be noted that the physiological levels of plasma ASP are also higher than insulin: 32.0 2.6nMASP25 vs 36±180pM insulin.29 The effects of ASP and insulin on glucose transport were not additive in the differentiated adipocytes whereas they are in human skin fibroblast and the L6 myotube models.9,10 This difference may be consequent to the differentiation induced changes in the level of expression of the various glucose transporters.  In the preadipocytes, although there was a trend towards additivity of the ASP and insulin effects, because the insulin effect (although significant) was modest, this was difficult to assess. Nevertheless, demonstration that ASP directly induces specific membrane transport of glucose is critical to documenting the mechanisms by which it increases triglyceride synthesis in adipocytes.

What I get from this is:  Insulin is not required for glucose to be transported into fat cells, knocking another leg out from under the whole insulin fat dysregulation theory.

Glyceroneogenesis v. Taubes

My greatest criticism of Taubes is that despite several years of "exhaustive" research, and a deluge of references in his book, the bulk of his "Adiposity 101" is either unreferenced, or based on decades old physiology texts and papers.

In this lecture (Slide 48 at around 46 min in) is his discussion of glycerol-3-P.  Taubes is a master of stating facts ... in a misleading way that (1) leads the listener/reader to incorrect conclusions, and (2) enables Taubes to use the "I never said that" out when challenged.

He first quotes a 1970's text on the Fatty Acid Cycle and shows an updated text of similar.  In both he highlights the need for glycerol-3-P to esterify FFA's to triglycerides.  This is true.  

However on Slide 48 he presents a bunch of cobbled together "facts" that are either not considered settled science or are taken out of context.  And I note that while he now (2009) lists glyceroneogenesis on his slide, the word never passes his lips.  He jumps right over this bullet point on the slide!!   I cannot help but think that he has been informed since the 2007 publication of his book that such a metabolic path exists.  But since acknowledging it would probably require scrapping this entire section of his lecture and derail his money train, he prefers to include a term on a slide in a long lecture and hope nobody notices.  Since this is a term few if any have a clue about, he's successful, and anyone who is reading his slides is likely to take at face value  his assertion that it is only a small amount.  If not outright deception in the name of financial gain, Taubes is at the very least displaying a degree of willful ignorance.

But maybe this whole glyceroneogenesis stuff is too recent to address, so Taubes is just relying on the old info b/c nothing concrete has come about.  Well, in addition to the comprehensive overview of the Fatty Acid - Triglyceride Cycle including glyceroneogenesis (2003), I recently came across this:

Glyceroneogenesis comes of age  2002


The science of glyceroneogenesis was being elucidated around the time that, presumably, Taubes began his lengthy research efforts following his Big Fat Lie NYT article.  How did he miss all of this?  And how, in 2009 can he continue to ignore this.

As I've blogged on previously,  the low carb nutritional state mimics the fasted state.  There is no reason to believe that the processes upregulated similarly for fasting and LC "fed" (gluconeogenesis, increased ketone formation, etc.) state would exclude glyceroneogenesis.  Indeed there is every indication that they are.

UPDATE:  It just got worse as I got my Sony ebook software working again to search GCBC for glyceroneogenesis.  Well, it's nowhere in the text, but it is right there in the title of one of his references.  The 2003 article linked to above.  I'm left to conclude this man is totally bereft of intellectual honesty.  

Glyceroneogenesis

Glyceroneogenesis and the Source of Glycerol for Hepatic Triacylglycerol Synthesis in Humans

Glyceroneogenesis,i.e. the synthesis of the glycerol moiety of triacylglycerol from pyruvate, has been suggested to be quantitatively important in both the liver and adipose tissue during fasting. However, the actual contribution of glyceroneogenesis to triacylglycerol synthesis has not been quantified in vivo in human studies. In the present study we have measured the contribution of glycerol and pyruvate to in vivo synthesis of hepatic triacylglycerol in nonpregnant and pregnant women after an overnight fast. 

After a 16-h fast, ∼6.1% of the plasma triacylglycerol pool was derived from plasma glycerol, whereas 10 to 60% was derived from pyruvate in nonpregnant women and pregnant women early in gestation. Our data suggest that glyceroneogenesis from pyruvate is quantitatively a major contributor to plasma triacylglycerol synthesis and may be important for the regulation of very low density lipoprotein triacylglycerol production. 

Our data also suggest that 3-glycerol phosphate is in rapid equilibrium with the triosephosphate pool, resulting in rapid labeling of the triose pool by the administered tracer glycerol. Because the rate of flux of triosephosphate to glucose during fasting far exceeds that to triacylglycerol, more glycerol ends up in glucose than in triacylglycerol. 

Alternatively, there may be two distinct pools of 3-glycerol phosphate in the liver, one involved in generating triosephosphate from glycerol and the other involved in glyceride-glycerol synthesis.

The synthesis of triacylglycerol in the liver, adipose tissue, and skeletal muscle following a meal is an important metabolic pathway for the deposition of fat and in the maintenance of energy homeostasis in all vertebrates. Even after an overnight fast in adult humans, and following a brief fast in newborn infants, a substantial re-esterification of fatty acids has been documented using isotopic tracer methods (1-3). The source of glycerol for the esterification of fatty acids in various tissues has generally been considered to be plasma glucose or glycerol; however direct evidence for such an inference has not been documented.

Triacylglycerol synthesis requires both fatty acids and a source of 3-glycerol phosphate. During fasting, the source of 3-glycerol phosphate can either be plasma glucose via glycolysis or glycerol released from the hydrolysis of triacylglycerol. In the adipose tissue in particular, the glycerol released from the hydrolysis of triacylglycerol cannot be re-utilized for the esterification of fatty acids because of absence of glycerol kinase. It has been proposed that during fasting adipose tissue generates the 3-glycerol phosphate required for triacylglycerol synthesis, either from glucose via glycolysis or, alternatively, from pyruvate via an abbreviated or truncated version of gluconeogenesis, termed glyceroneogenesis (4-7). The key enzyme in this pathway is the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK;¹ EC 4.1.1.32). The transcription of the gene for PEPCK is stimulated by cAMP during periods of fasting (8, 9), resulting in an increase in enzyme activity in both adipose tissue and liver. In isolated epididymal adipose tissue from the rat, the rate of re-esterification of free fatty acids was greatly increased by the provision of a glyceroneogenic precursor such as pyruvate (10). In addition, hepatic glyceroneogenesis has been shown to account for ∼89% of glyceride-glycerol in the triacylglycerol synthesized by rats fed a high protein diet (11).

There has not been a quantitative analysis of the relative rates of glyceride-glycerol synthesis from its precursors, plasma glycerol, pyruvate, or glucose in humans. In the present study we have quantified the relative contribution of plasma glycerol and pyruvate (plus lactate, alanine, etc.) to glyceride-glycerol in nonpregnant and pregnant women during fasting. Pregnant women were studied because of the higher concentration of plasma triacylglycerol during pregnancy, particularly in the third trimester. Our data show that the source of glyceride-glycerol following a brief fast is predominantly pyruvate. Because the synthesis of glucose and glyceride-glycerol from plasma glycerol share common enzymatic reactions, our data also suggest a functional separation of the pathways of glycerol entry into the liver and the 3-glycerol phosphate precursor pool for triacylglycerol synthesis.

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When doing LC, our metabolisms are essentially the same as the fasted state.  More than half of the triglycerides that are broken down to free fatty acids are re-esterified to triglycerides even in the fasted state.  Where do we get the G3P?  Glyceroneogenesis.  And there's that pesky PEPCK again.

This blows one of Taubes' central theories out of the water!