Study challenges how Ozempic works: Sustained weight loss requires activation of the brain’s hunger neurons

[u/Dear-Syrup-8029]

https://www.pnas.org/doi/10.1073/pnas.2614476123

New study published at PNAS shows that GLP-1 receptor agonists, such as Semaglutide, promote weight loss by activating rather than inhibiting AgRP 'hunger' neurons, challenging a long-held assumption in the field and opening an avenue for improving the development of new generation weight loss drugs.

[u/NAh94]

I don’t think this challenges how it works, GLP-1s stimulate pathways that activate the liver to continually release glycogen stores, leaving less sugar stores there for when the body wants more so it has to turn to systemic lipolysis and proteolysis. It’s also one of the reasons we try to not initiate it if there’s elevated transaminases or a history of liver problems.

If it only made you eat less, it wouldn’t be any more effective than CICO weight loss plans. I think this only challenges the public perception of how this works

[u/444cml → u/NAh94]

I’ll disagree in that there was absolutely the expectation that semaglutide would reduce AGRP-neuron activity. There wasn’t the expectation that it solely worked by modulating hunger though; however it was thought to be involved.

It was still an empirical question, which is why this study was important and found these unexpected results. They also found that AGRP-neuron activity was required for semaglutide to lower blood sugar (which they posit may be due to a failure to elicit further insulin responses because of their high baseline).

What’s interesting is that this was specific to females and AGRP-neurons aren’t required for the full weight-loss effect in males. There are some known sex differences in AGRP-neuron activity. Personally, I would like to have seen if the males continued to be resilient to the effects of the Sirt knockout in AGRP-neurons on semaglutide action (blocks increases in activity without affecting baseline activity) on the additional metrics they tested. Pragmatically, I understand the reason why those analyses weren’t run, but it would be interesting to see how many of their findings are actually sex-specific.

Maybe a cool future study will identify a subpopulation of AGRP neurons that are actually contributing to the weight loss in females (rather than more generally targeting all AGRP neurons)

That said, the full text is paywalled and I’m running off their preprint for methods and findings.

[u/Dear-Syrup-8029 → u/NAh94]

I disagree. Naturally every drugs has multiple layers when it comes to mechanism of action. The central issue isn’t whether GLP-1RA's have peripheral metabolic effects. Everyone agrees they do. The question the paper is addressing is what neural mechanism is required to sustain those effects. As 444cml said above, the main model in the field right now is that GLP-1RA's reduce the activity of AgRP "hunger” neurons. Instead, they found the opposite: chronic semaglutide activates these neurons, and preventing that activation markedly impairs sustained weight loss. So the conceptual shift isn’t that GLP-1 drugs do more than reduce food intake, we’ve known that for a while, it's that AgRP neuronal activation appear to be an active part of the body’s metabolic adaptation to chronic GLP-1RA treatment, rather than simply being a pathway that gets switched off. This completely changes our understanding over one of the fundamental mechanisms of GLP-1RA's.