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.
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
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.
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)."
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
Now we're getting to it.
ReplyDeleteI was aware of the fact that oxidized LAs are PPAR gamma ligands, but I didn't know they affected this.
I did see a paper showing that HNE forms adducts with another Aquaporin, #3, which doesn't do it any good, and suspected the same might be true with #7.
Now please cut it out with the posting for a little bit, so I can finish my "rebuttal"/attempt to move the ball further down the field.
(Just to whine, please don't post these out of sequence!)
I have a different take on "futile cycles". I prefer the name "substrate cycles". It's been pointed out that they can provide leverage.
ReplyDeleteJeremy Berg et al. [illustrate it this way](https://www.google.com/books/edition/Biochemistry_Fifth_Edition/uDFqAAAAMAAJ):
> Suppose that the rate of conversion of A into B is 100 and of B into A is 90, giving an initial net flux of 10. Assume that an allosteric effector increases the A → B rate by 20% to 120 and reciprocally decreases the B → A rate by 20% to 72. The new net flux is 48, and so a 20% change in the rates of the opposing reactions has led to a 380% increase in the net flux.
So to NOT consider secondary effects of this type of "antidiabetic agents" notable. Does anyone know what happens to the glycerol backbones that are released as fat enters adiopcytes? Is part of it stored on the exterior of the cell wall for later use?
ReplyDeleteI know there are a lot of people pushing the balance of O3-O6 - but I'm not buying it. The arachnidonic => pro inflammatory PGs is only one metabolic pathway, when the reality is never that simple.
We never evolved to eat huge amounts of foods full of LA.
Hi Tucker, yes, I certainly see 4-HNE at low levels as a facilitator of the insulin signalling cascade and it came as no surprise that it activates PPAR gamma. I would expect it to do the reverse at higher levels. Obviously, assuming disabling aquaporins is a mechanism, then it would have to disable activating steps further down the line, at those higher levels...
ReplyDeleteAmber and karl, I was thinking more simply along the lines that triglycerides are phosphate free so trigs to glycerol and FFAs has no ATP cost. The re esterification step is not the reverse and the glycerol, from any source, requires phosphorylation using ATP. The cost of the process, in ATP, could have been used to make babies. Assuming it wasn't simply supplementing/part replacing the "waste" of delta psi through UCP-1 for thermogenesis...
ReplyDelete