The Triglyceride/Fatty Acid CycleS and the role of Glyceroneogenesis

Thanks to a certain journalist, much of the discussion of fat tissue metabolism on the internet presents a very myopic view of things taken out of context.  One example of this, is that in Chapter 22 of GCBC, Taubes lists all of the hormones acting on adipocytes.  The caption on the graphic reads:
In 1965, hormonal regulation of adipose tissue looked like this: at least eight hormones that worked to release fat from the adipose tissue and one, insulin, that worked to put it there.
Let's leave aside for a moment that in the four subsequent decades preceding the writing and publication of his book, probably the most potent regulatory hormone of fat mass, leptin, was discovered.  Let's also leave aside all of the other adipokines (the term for the collection of hormones and peptides produced by adipocytes most of which appear to be secreted).   There's a lesson to be learned solely from Taubes' narrow, outdated view.  Under the title "Hormones that promote fat mobilization", Taubes lists:   Epinephrine, Norepinephrine, Adrenocorticotropic hormone (ACTH), Glucagon, Thyroid-stimulating hormone, Melanocyte-stimulating hormone, Vasopressin, and Growth hormone.  In the opposing column under the title "Hormones that promote fat accumulation", he lists only one:  Insulin.  He precedes this with what he seems think is information either unbeknownst to or forgotten by researchers in the field -- that fatty acids are continually cycling in and out of fat tissue, and that caloric excess is not required for deposition, nor is caloric deficit required for mobilization.

Among their discoveries is that both dietary fat and a considerable portion of the carbohydrates we consume are stored as fat—or, technically, triglycerides—in the adipose tissue before being used for fuel by the cells. These triglycerides are then continuously broken down into their component fatty acids, released into the bloodstream, moved to and from organs and tissues, regenerated, and merged with fatty acids from the diet to reform a mixture of triglycerides in the fat cells that is, as Schoenheimer put it, “indistinguishable as to their origin.” Fat stored as triglycerides in the adipose tissue, and the fatty acids and triglycerides moving through the bloodstream are both part of the same perpetual cycle of fat metabolism. “Mobilization and deposition of fat go on continuously, without regard to the nutritional state of the animal,” as the Israeli biochemist Ernst Wertheimer explained in 1948, in a seminal review of this new science of fat metabolism. “The ‘classical theory’ that fat is deposited in the adipose tissue only when given in excess of the caloric requirement has been finally disproved,” Wertheimer wrote. Fat accumulates in the adipose tissue when these forces of deposition exceed those of mobilization, he explained, and “the lowering of the fat content of the tissue during hunger is the result of mobilization exceeding deposition.”   The controlling factors in this movement of fat to and from the fat tissue have little to do with the amount of fat present in the blood, thus little to do with the quantity of calories consumed at the time. Rather, they must be controlled, Wertheimer wrote, by “a factor acting directly on the cell,” the kind of hormonal and neurological factors that Julius Bauer had discussed. Over the next decade, investigators would begin to refer to these factors that increase the synthesis of fat from carbohydrates and the deposition of fat in the adipose tissue as lipogenic, and those that induce the breakdown of fat in the adipose tissue and its subsequent release into the circulation as lipolytic.  
See?  It's all a balance of a continual cycle.  And in 1965 we knew of one hormone that favors deposition, and eight that favor mobilization.  So we can do a mass balance equation on the adipocyte:

Adipocyte Mass = Deposited TG Mass - Mobilized FA Mass

But only insulin regulates this ... nevermind the other eight hormones involved.  Nothing to see there?!  But where I'm going with this in the next few days is to flesh out some thoughts on the Triglyceride/Fatty Acid cycle -- or rather cycleS -- and the role of glyceroneogenesis in the regulation of, at the very least, the cycle occurring within the adipocyte.  To this end, below I've augmented the TAG/FA cycle diagram from the 2003 Reshef article referenced in GCBC.  

So in the coming days (weeks?) I'll address in more detail the base of the blue cycle inside the adipocyte.  In the fed state, the pool of FFA is comprised of incoming fatty acids and triglycerides (TAG,TG) that have undergone lipolysis by hormone sensitive lipase (HSL).  The insulin elicited by a meal acts to suppress HSL so this pool is largely contributed to from dietary fatty acids.   In the fasted state, this internal FFA pool is comprised largely of fatty acids liberated from stored TAG.  But here's the thing.  What is the fate of the fatty acids in this pool, fed or fasted?  Well, a considerable proportion is always esterified into TAG for storage.  And what controls that?  Answer:  Glyceroneogenesis through the amount and activity of PEPCK-C enzyme that regulates the level of glycerol-3-phosphate, G3P, produced via glyceroneogenesis.  And what regulates this enzyme and metabolic pathway?  No ... not insulin.  Glucocorticoids -- something I plan to expand upon as we go forward here.  

Let's revisit that Adipocyte Mass Balance again:  ∆ Adipocyte Mass = Deposited TG Mass - Mobilized FA Mass.  Note that the last term is "mobilized" -- as in exiting or escaping the fat cell.  Lipolysis by HSL is not sufficient to mobilize a fatty acid ... it must "escape" re-esterification.  And indeed, when you look at the action of those other 8 hormones from Taubes' description, we see that mobilization is not regulated by insulin.  Insulin (or rather the lack thereof suppressing HSL) fills the reservoir with FFA, what happens to these FFA is controlled by other hormones, and there are two fates:  out or re-esterification.  And imagine my surprise (not really) to discover there is a feedback loop between leptin and glucocorticoids in the human adipocyte.  Yes folks, there is a lot to come on this topic!


bentleyj74 said…
Yay! Looking forward to it :)
MM said…
Me too! I'm very much looking forward to learning more about this!
Ed Lee said…
Cool. I hope you will touch on the transportation of fatty acids in serum, because I am trying to understand when and why FA is transported either as NEFA or as TG wrapped in lipoprotein particles. I'm particularly interested in exploring the role of the liver in producing TG carrying VLDL particles.

I know there has been heavy discussion in the blogosphere of the regulation of circulating glucose levels, and the role of carbs and insulin, but hopefully during this series you will shed some light on the regulation (if any) of circulating TG and NEFA levels. Thanks in advance, I'm looking forward to your series, as I'm sure I will learn something or two.

Q: "Insulin (via HSL) fills the reservoir with FFA". Can you explain this "reservoir"? It's been a while since I read WWGF, but I think the explanation is that TG is too large to pass through fat cells, so it needs to be broken down like a big piece of furniture. Is there some sort of reservoir in the fat cells where FFA pool, and they can either exit the cell, just stay there in this reservoir, or get re-esterified into TG?
Susanne said…
I don't know about your fancy CW pharma-shill science, this evening I cut my thumb as I was slicing zucchini, which is all the proof I need that CARBS KILL. Also, on a completely related note, I blame you and your ilk* for introducing me to the live-action trainwreck which is the Mark's Daily Apple nutrition forum. I am now as hooked on it as hopelessly as on the most sordid of TV reality shows that I always swore I was too civilized to watch. Except on Jersey Shore the answer rarely involves drinking a few extra slugs of coconut oil and a personal anecdote about how dropping wheat saved your family, no matter what the "so-called published experts" say.

*it may have been Weight Maven actually.
CarbSane said…
Hey Ed, One of my peeves from the inception of this blog (and before) was that nobody seems to be concerned in the LC community with free fatty acids. Fats have very limited solubility in body fluids (blood, cytosol = cell fluid) and are able to pass through membranes without transporters. Therefore they are "toxic" in elevated amounts even if not directly so. What this does is force the mitochondria to burn fat even when glucose availability is high, but the fat burning is also inefficient and incomplete leading to build-up of intermediary metabolites: ceramides, diacylglycerols, etc. So in all realms, our bodies seek to "deactivate" fatty acids by esterifying them into TAG until needed. This way the levels can be regulated, and thus transport regulated, etc. Even free fatty acids in circulation are not "free", they are bound to albumin, but this binding is easily broken thus making these molecules more readily available for energy if needed. But there is limited "solubility" of these (I did the calculation once -- if you look at the chrono list of posts, it was called something like a Matter of Concentration.) which is why most fats are transported as triglycerides wrapped in protein shells -- lipoproteins -- that are "dissolved" (not proper term, but OK for this purpose) in the blood.

Our FFA levels are supposed to be controlled by release from adipose tissue. VLDL from the liver is the return route of excesses in TAG/lipoprotein form.

Lastly, in terms of the "reservoir", that was a bit of a metaphor, however one can envision there's a little pool of FFA that has one of two fates -- export to circulation, or esteri/re-esterification. If you look on that same list for Triglycerides, I did a 3 part series on that. The model in the major paper on which that was based (I think it's Part I) describes a triglyceride pool in the liver. I imagine this to be analogous.
CarbSane said…
Ahh! Death by zucchini almost befell me once! Mandolin sans guard ... getting to the end ... middle finger ... tip ... slice ... ouch!
Probably wasn't me! I've never been to the MDA forum. I find forum threading to be less than satisfactory, so have never been active in any.
Susanne said…
Apologies all around then. I consoled myself after the squash with some homemade seafood enchiladas, Mexican brown rice, lard-free black beans, and some nightshade-heavy salsa. Fortunately, as a trained archaeological professional, I eat a Bronze Age diet, so I am not afraid of NAD. :)
Papa Carlo said…
Q&A with Gary Taubes about Leptin:

11:45 Comment From Victoria Your two books focus primarily on insulin. The (real) science is fascinating, but now I’m curious about leptin. Do you have anything to say about leptin, or maybe other hormones?

11:49 Gary Taubes: Hi Victoria,I’ve mostly left leptin out of my books because I think it’s effects are downstream of insulin. Leptin is secreted by the fat tissue and the more fat we have the more leptin we secrete. Leptin then effects hunger/satiety and energy expenditure. But what we want to know is what makes us accumulate the fat in the first place, and that’s the insulin. In fact, leptin secretion is also regulated directly by insulin secretion and how much glucose is metabolized in the fat tissue, and both of those are controlled by the carb content of the diet. So the only way to effect leptin secretion and resistance to leptin, far as I can tell, is by bringing down insulin levels and inhibiting insulin secretion. There are other hormones that play a role directly in fat accumulation and those I discuss — sex hormones, in particular — and I do discuss those because they’re directly relevant to fat accumulation.

from here:
John Smith said…
Great fatty acid article Ever I read :)

of fatty acids