GLP-1 agonists

It was Bill Lagakos who tweeted this paper recently:

Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): Exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials

The drug itself is of no interest as it will, without doubt, result in Unintended Consequences. But the GLP-1 agonists do seem to work as weight loss/diabetes management drugs, which is strange. The paper per se describes clinical work and looks to be written by clinicians so is unlikely to provide any sort of insight as to mechanism(s) of action.

It is worth thinking about how a drug which increases insulin synthesis, insulin reserves and insulin secretion in response to glucose might actually cause weight loss. Really, it shouldn't... Everything is against this. But it does.

From this paper

Regulation of Adipocyte Formation by GLP-1/GLP-1R Signaling

it appears that the GLP-1 agonists activate the formation and preservation of new adipocytes, much as the glitazones do:

"These findings, combined with our results, strengthen the notion that GLP-1 or liraglutide regulate adipogenesis via suppression of apoptosis and stimulation of proliferation."

So the GLP-1 agonists stimulate adipose hyperplasia meaning you develop lots of small adipocytes which are much better able to act as a sump for calories. There appears to be a shift of fatty acids out of pre-existing hypertrophied adipocytes, and out of ectopic fat deposition sites too, and in to these spanking new baby adipocytes.

Why don't you get hungry and fat, as you do with the glitazone drugs?

You should do.

This paper used ob/ob mice (so caution) 

GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis

and confirms the presence of those small adipocytes in white adipose tissue under GLP-1 agonists, a lack of visceral fat hypetrophy and, interestingly, a down-regulation of the gene for the fatty acid synthase enzyme, crucial for de novo lipogenesis. Not only are the mice used ob/ob but the "high fat" diet is unspecified, even following all three refs they cite as describing it. So even more caution about these people. But in both 3T3-L1 "adipocytes" and in real ob/ob adipocytes, fatty acid synthase gene expression is down regulated. Their suspicion is that suppressed de novo lipogenesis limits adipocyte hypertrophy. They have no insight as to why.

And what regulates fatty acid synthase gene expression? Did I hear insulin from the back there? I hope so.

Let's summarise:

GLP-1 agonists induce the production of large numbers of small, highly insulin sensitive adipocytes which don't become distended. They don't distend (probably) because fatty acid synthase gene expression is down-regulated. I consider this to be a flag for suppressed insulin signalling. Suppressed insulin signalling leads to a lean phenotype. So an insulin sensitising agent reduces insulin controlled gene expression to avoid obesity. WTF?

After this preamble let's get to an abstract which was the first hit of my PubMed search based on GLP-1, adipocyte and ROS:

Semaglutide (GLP-1 receptor agonist) stimulates browning on subcutaneous fat adipocytes and mitigates inflammation and endoplasmic reticulum stress in visceral fat adipocytes of obese mice

I don't have the full text but the abstract alone is quite informative. Here are the relevant statements:

"Semaglutide enhanced multiloculation and uncoupled protein 1 (UCP1) labeling in obese mice [adipocytes] ..."

and

"Besides, semaglutide activated adipocyte browning, improving UCP1, mitochondrial biogenesis, and thermogenic marker expressions help weight loss."

I think it is reasonable to accept that GLP-1 agonists activate uncoupling. We have know for a very long time, since the days of di-nitrophenol and more recently BAM15, that uncoupling reverses metabolic syndrome.

For the time being I will just leave it that GLP-1 agonists decrease insulin's action secondary to uncoupling. In this they are similar to the uncouplers DNP and BAM15 and also to metformin which blocks insulin's action, not by uncoupling but by blockade of the glycerophosphate shuttle. All work via decreased ROS generation.

Reduction of insulin signalling is intrinsic to weight loss.

Quite how decreasing insulin signalling via uncoupling can be made to show an increased insulin responsiveness (right down to the level of Akt phosphorylation) is an interesting question. I got part way through discussing this next using a paper on BAM15 but it made the current post so long and unwieldy that it needs a post of its own.

Peter

Throw away comment (I have not been through these papers!). Many people are reported to be using a GLP-1 agonist for weight control. It's probably working by activating/generating UCP-1, which is cool. At the same time it is generating lots and lots of new baby adipocytes, which stay small through uncoupling.

Currently the risk of promoting breast cancer by GLP-1 agonists is taken sufficiently seriously to have promoted a systematic review and meta-analysis to bury said risk:

Do GLP-1 Receptor Agonists Increase the Risk of Breast Cancer? A Systematic Review and Meta-analysis

Sadly metabolic reality couldn't give an F about systematic review and meta-analysis:

Glucagon-like peptide-1 receptor activation by liraglutide promotes breast cancer through NOX4/ROS/VEGF pathway

and eventually these drugs will be withdrawn. So what will happen to folks with years of adipocyte hyperplasia, where individual cell hypertrophy has been suppressed? Their very numerous small adipocytes will, without their uncoupling drug, become enormous. People will become hungry as they develop hypertophy of all of those lovely tiny insulin sensitive adipocytes. Oops. It's gonnabe bad, but that's years down the road.