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   There's a lesson to be learned solely from Taubes' narrow, outdated view.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 et.al. 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!