Semaglutide works through PACAP-expressing brainstem neurons that promote fat loss over muscle loss | Research

The takeaway

Semaglutide activates Adcyap1+ (PACAP-expressing) neurons in the dorsal vagal complex that specifically promote fat utilization over lean mass loss, with ablation of these neurons largely reversing semaglutide's anti-obesity effects.

Fat loss neurons identified
Semaglutide works through specific PACAP-expressing brainstem neurons that preferentially promote fat over lean mass loss—a key finding for designing better weight loss drugs

What the researchers found

Semaglutide activates AP/NTS Adcyap1+ neurons. Reactivation mimics drug effects (↓food intake, ↓weight, ↑fat utilization, CTA). Ablation reverses drug effects in lean + obese mice. Adcyap1+ neurons: promote fat > lean mass loss. Modest CTA contribution. AP GLP-1R neurons → NTS Adcyap1+ neurons → downstream satiety.

Why it matters

Understanding the exact neurons mediating semaglutide's effects enables design of next-generation drugs that selectively activate these neurons—maximizing fat loss while minimizing muscle loss and nausea.

How the study worked

Semaglutide-responsive neuron mapping. Chemogenetic reactivation (DREADD). Adcyap1+ neuron ablation. Lean and DIO mice. Body composition analysis. Conditioned taste aversion.

What this study cannot tell us

Mouse study. Ablation is permanent—does not model reversible drug effects. Adcyap1 expression identifies but may not fully define the critical population. Human brainstem circuits may differ.

How to read the evidence

Rigorous neuroscience study with chemogenetics, ablation, and body composition analysis. Strong mechanistic evidence in mice.

When this study was published

Published in 2025.

The bigger picture

PACAP-expressing brainstem neurons are the critical mediators of GLP-1 drug-induced weight loss. Selectively targeting these neurons—rather than broadly activating all GLP-1 receptors—could produce drugs with better body composition outcomes and fewer side effects.

Questions still open

Could drugs targeting Adcyap1+ neurons specifically provide superior weight loss?
Does PACAP itself mediate some of semaglutide's effects?
Would preserving these neurons from damage improve long-term GLP-1 drug efficacy?

Common questions

How does semaglutide actually cause weight loss in the brain?

This study found semaglutide activates specific neurons in the brainstem that express the neuropeptide PACAP. These neurons receive signals from GLP-1 receptor-expressing neurons and then activate satiety circuits that reduce appetite. Crucially, they promote fat burning rather than muscle loss.

Could this lead to better weight loss drugs?

Yes—directly targeting these PACAP-expressing neurons could produce drugs that maximize fat loss while minimizing muscle loss and taste aversion (which contributes to nausea). When researchers ablated these specific neurons, semaglutide's effects were largely reversed, proving they are the critical mediators.

Read the original research

Semaglutide effects on energy balance are mediated by Adcyap1+ neurons in the dorsal vagal complex.

Cell metabolism, 37(7), 1530-1546.e6

View on PubMed ↗Publisher’s paper ↗

Citation

Teixidor-Deulofeu, Júlia; Blid Sköldheden, Sebastian; Font-Gironès, Ferran; Feješ, Andrej; Ruud, Johan; Engström Ruud, Linda. (2025). Semaglutide effects on energy balance are mediated by Adcyap1+ neurons in the dorsal vagal complex.. Cell metabolism, 37(7), 1530-1546.e6. https://doi.org/10.1016/j.cmet.2025.04.018