Protons (80) The Carpentier Paradox (Carpentier III)

Preamble.

Direct quotes from Carpentier:

"Raglycerol, a marker of total AT lipolytic rate..."

"Plasma glycerol appearance was lower in IGT..."

"Postprandial palmitate appearance (Rapalmitate) was higher in IGT..."

If we combine the second two statements we can re write the findings as:

In people with IGT the rate of lipolysis is decreased (glycerol release) and simultaneously increased (FFA release) in the post prandial period.

A paradox. Oooh exciting! It would have made a great title for the paper.

So I wrote this post.

Just a one liner based on Tucker's link:

Obesity and metabolic perturbations after loss of aquaporin 7, the adipose glycerol transporter

discussing this paper

Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase

If you knock out the glycerol/water transporter aquaporin 7 you get an obese mouse model, late onset.

This KO increases the glycerol content of adipocytes and, in all probability, drives the reaction

glycerol + ATP <-> glycerol-3-P + ADP

to the right, on the basis of increased glycerol concentration. The enzyme is glycerokinase.

This using a sledge hammer to move reaction kinetics and I doubt it has much to do with generic obesity.

But it does demonstrate that if you drive glycerol-3-phosphate formation you can drive obesity. Then comes this little snippet from the discussion:

"Lazar and coworkers demonstrated that thiazolidinediones markedly increased Gyk [Glycerokinase] mRNA level in adipocytes, resulting in triglyceride accumulation through enhancement of the conversion of glycerol into glycerol-3-P (21)."

This is ref 21 

A futile metabolic cycle activated in adipocytes by antidiabetic agents

The glitazones allow "futile" cycling of FFAs from triglycerides back in to triglycerides WITHOUT releasing the glycerol from the cell. Like aquaporin 7 KO mice but without all of that complicated genetic engineering.

Aside: "Futile" cycling is anathema to evolution. You either have an unavoidable thermogenic effect of an essential process, like protein catabolism, or you have a useful thermic effect like thermogenic uncoupling. The latter is derived from essential uncoupling to avoid damaging elevations of delta psi in mitochondria, wastefull but essential. Futile cycling without fulfilling a need or without an essential underlying process wastes energy which should be used to make babies. Survival of the fecundest is how it goes. "Futile" cycling is pathology. End aside.

So you cannot use glycerol release as an index of total lipolysis if subjects are taking glitazones to become fat. Oops, I mean to become insulin sensitive. Ah, is there any difference?

Which brings us right back to Carpentier's failure to discuss the *fall* in glycerol release from adipocytes concurrent with the *rise* in FFA release in the post prandial period.

Of course Carpentier's subjects weren't taking pharmaceutical activators of PPARγ.

But they were Canadians who had managed to eat sufficient linoleic acid to get themselves in to prediabetes.

Which begs the question: Is linoleic acid a glitazone mimetic? Well, no. But it generates functional PPARγ activators which *are* glitazone mimetics. You know, 9-HODE, 13-HODE and, of course, 4-HNE. All of which, at the correct concentration, would activate PPARγ and allow "futile" cycling of intra-adipocyte FFAs back to triglycerides without releasing their glycerol.

I'm embarrassed that I was unaware of this.

Carpentier is being paid a group leader's salary to be unaware of it. Also, who the hell scrutineered the paper?

Oops. And oops.

Peter