What Does Insulin Regulate Anyway?

I'm not a fan of arguments over semantics, but at the same time I can be a stickler for the notion that "words count" at times.  When I hear the word regulate, as in A regulates B, I substitute the word control.  So A controls B.  And this ultimately means that A determines what B is.  

Part of TWICHOO* is that insulin "fundamentally regulates" fat accumulation.  What Taubes is saying is that insulin regulates fat tissue mass.  Insulin controls fat tissue mass, and ultimately that means that insulin levels determine how fat you are.    *Taubes Wrong Insulin Carbohydrate Hypothesis Of Obesity

The TAG/FA Cycle

To state his case, Taubes zeros in on the TAG/FA cycle that occurs continually in the fat cell, and the known fact that insulin plays a role in  this cycle.  This is not in dispute, although the relative weight of insulin's actions on the outcome may be somewhat argued in these circles.

The full TAG/FA cycle is pictured at right (from Reshef et.al. 2003) -- the version Taubes discusses in GCBC.  We see that triglycerides and free fatty acids are constantly cycling both within the fat cells, and between the fat tissue and the liver and muscle tissues.  Some of the released fatty acids are re-esterified without leaving the fat cell, others are sent out in circulation and later returned to sender by the liver (VLDL).

Insulin stimulates the esterification of fatty acids into triglycerides on the "IN" side of the fat tissue, and suppresses the lipolysis of stored triglycerides by HSL on the "OUT" side.  It's a no-brainer then, that insulin works to put fat into and keep fat in your fat cells.  Game-set-match insulin, cased closed, QED, insert cliche here.

Let's assume insulin is the only hormone ...

Even though it is known that other hormones are involved in regulating this cycle, let's stipulate, for the sake of simplicity in this post, that insulin is the sole regulator of the TAG/FA cycle.  Let's also stipulate that uptake of dietary fat is regulated solely by insulin.  Repeat:  These are stipulations for the sake of a simplified argument, not statements of fact.

The question is, why is insulin doing this?  Is it to control how much fat you accumulate ... in other words to regulate the size of your fat stores?  It would appear not.

Where's the feedback?

The pancreas produces insulin.  If it produces too much and you get too fat, does the fat tissue signal back to the pancreas to stop producing so much?  Apparently not, or the obese would have a lower insulin response to stimuli, right?  Does the fat tissue produce anything that directly feeds back to the pancreas (e.g. in the form of direct pancreatic sensor) to tell it to shut down production a bit?  Again, apparently not.  I've not come across any mention in the literature of specific adipokine receptors on beta cells.  (Adipokines like TNF seem to mediate beta-cell death, but not via a specific receptor, and this pathological action is not the sort of physiological feedback we're looking for.)

What does the pancreas sense?  Well, for one, glucose levels ... we'll get back to that.  But what else?  Free fatty acids!!  We've discussed here many times before how fats, per se, do not elicit an insulin response but how NEFA do.  Remember, NEFA (non-esterified fatty acids, or free fatty acids, FFA) being the form of circulating fats that are taken up by cells and used for energy.   The point of control of NEFA levels is mostly at the release point from fat tissue.  Aside from the liver, which secretes fats largely as triglycerides in VLDL particles, adipose tissue is the only other tissue from which fatty acids flow out.  When NEFA levels are too high, excessive fatty acids are delivered to the cells and metabolic mahem within the cells ensues.  

So what does insulin actually regulate?  

Insulin regulates circulating levels of free fatty acids.  And how does it do this?  By acting on fat cells to control the rate of release and uptake of fatty acids.  How is this intended to be self-regulating?  By a feedback loop.  

Low circulating NEFA → reduced insulin → increased circulating NEFA (↓uptake/esterification, ↑HSL/release) → High circulating NEFA → insulin secretion → decreased circulating NEFA  (↑uptake/esterification & ↓HSL/release ) → low circulating NEFA ... rinse, repeat, etc.

Frankly, my dears, your pancreas doesn't give a damn about your fat tissue mass.  It's trying to regulate your NEFA levels.   Insulin ultimately has virtually no control over your fat mass.

What else does insulin regulate?  Insulin regulates circulating (blood) glucose levels.  Hmmm ... and in an exquisitely reciprocal fashion, I might add, to how it regulates NEFA when all things are running smoothly.  It does this by acting mostly on the liver and muscle cells to stimulate glucose uptake, inhibit glucose supplied by the liver (suppresses both gluconeogenesis and glycogen breakdown) and glucose disposal (increases glycogen synthesis and glycolysis or glucose burning).  Is there a feedback loop?  Certainly!  Insulin is secreted in response to high levels, and dialed back when levels drop.  When insulin levels drop the liver now delivers glucose (glycogen breakdown and gluconeogenesis) to circulation.  

And again, frankly, my dears, your pancreas doesn't give a damn about your liver either.  If too much glucose builds up to force de novo lipogenesis, or excessive NEFA lead to triglyceride build up in the liver -- aka fatty liver -- that's not your pancreas' concern.  It is only trying to regulate your circulating blood glucose and fatty acid levels.

So what regulates fat tissue mass?

The regulation of fat accumulation, fat tissue, requires a feedback from the fat tissue itself.  We know of one.  It's called leptin.  Too much fat accumulates when we take in more energy than we expend.  As fat accumulates, the fat cells secrete more leptin.  Leptin signals you to eat less and for the body to burn fuel at a faster rate (increases basal metabolism, boosts fatty acid oxidation).  That, folks, is regulating fat mass.   There may be other adipokines involved, and the leptin story turns out to be more complicated than early animal models would have predicted, but if we're looking for a feedback system that would appear to control fat mass, it is one involving leptin.

So ... to sum up:  

What does insulin regulate?  Nothing really.  It is the signalling molecule by which the pancreas regulates things, but let's not quibble too much over those semantics, shall we?

Insulin regulates circulating levels of glucose and 

NEFA to ensure a ready supply of energy at all times.  

---

Part II