Semaglutide Doesn't Rewire the Brain's Appetite-Suppressing Neurons, Study Finds | Research

The takeaway

Anti-obesity drugs like semaglutide don't appear to change the proportion of appetite-suppressing POMC neurons in the brain, suggesting they work through other mechanisms.

No change
Neither semaglutide nor LiPR altered the proportion of appetite-suppressing POMC neurons in human stem cell-derived or mouse brain tissue

What the researchers found

Semaglutide and lipidized prolactin-releasing peptide (LiPR) — two anti-obesity compounds — did not change the proportion of POMC-expressing neurons when applied to human stem cell-derived hypothalamic neurons or mouse brain tissue. LiPR also did not alter POMC neuron shape, gene expression patterns, or the generation of new POMC neurons in mice. This suggests anti-obesity medications do not work by rewiring the brain's appetite-suppressing neuron population.

Why it matters

Scientists have wondered whether weight-loss drugs like semaglutide might permanently reshape the brain's appetite circuits by changing which neurons mature into appetite-suppressing cells. This study suggests they don't — the drugs appear to work through other mechanisms rather than by altering the fundamental composition of hypothalamic neurons. This is reassuring because it means the drug effects are likely reversible rather than structural.

The numbers in context

No change in POMC+ neuron proportion with semaglutide · No change in POMC+ neuron proportion with LiPR · No change in POMC neuron morphology · No change in metabolic gene expression

How the study worked

Researchers grew hypothalamic neurons from human induced pluripotent stem cells (iPSCs) in the lab and exposed them to semaglutide or LiPR during their maturation phase. They then measured the proportion of POMC-expressing neurons. In a separate experiment, they administered LiPR to live mice and examined newly generated POMC neurons in the medial basal hypothalamus.

Who was studied

Human iPSC-derived hypothalamic neurons (in vitro) and adult mice (in vivo)

What this study cannot tell us

This study used iPSC-derived neurons in a dish, which may not fully replicate how neurons behave in a living human brain. The mouse experiments only tested LiPR, not semaglutide. The study examined only POMC neurons and did not assess other neuron types that might be affected. Treatment duration and dosing in the lab setting may not reflect long-term clinical use.

How to read the evidence

This is an early-stage study combining in-vitro human cell experiments with limited mouse data. While the human iPSC model is innovative, lab-grown neurons don't fully replicate brain conditions, and the findings are negative — showing absence of effect rather than confirming a mechanism.

When this study was published

Published in 2025, this is very recent research addressing a timely question about how GLP-1 drugs affect the brain as their use has exploded worldwide.

The bigger picture

As millions of people take GLP-1 drugs for weight loss, a key question is whether these medications cause permanent changes to brain circuitry. This study provides early evidence that semaglutide does not fundamentally alter the brain's appetite neuron population — suggesting the appetite effects may be pharmacological rather than structural, which could explain why appetite often returns after stopping the medication.

Questions still open

If semaglutide doesn't change POMC neuron populations, what specific neural mechanisms does it use to reduce appetite?
Does long-term semaglutide use cause other types of brain changes that weren't measured in this study?
Could the return of appetite after stopping GLP-1 drugs be explained by the lack of permanent neuronal rewiring?

Common questions

Does semaglutide permanently change your brain?

This study suggests it does not — at least not in terms of the appetite-suppressing POMC neuron population. Neither semaglutide nor another anti-obesity peptide altered the proportion of these key neurons in human or mouse brain tissue, indicating the drug's appetite effects likely work through temporary signaling rather than structural brain changes.

What are POMC neurons and why do they matter for weight loss?

POMC neurons are brain cells in the hypothalamus that produce chemicals telling your body to stop eating and burn energy. They're a key part of the brain's appetite control system. Scientists wondered if weight-loss drugs might work by increasing these neurons, but this study found they don't — the drugs appear to work through other pathways instead.

Read the original research

Anti-obesity compounds, Semaglutide and LiPR, and PrRP do not change the proportion of human and mouse POMC+ neurons.

PloS one, 20(8), e0329268

View on PubMed ↗Publisher’s paper ↗

Citation

Jörgensen, Sara K M; Surridge-Smith, May; Jones, Kimberley; Maletínská, Lenka; Allen, Nicholas D; Petrik, David. (2025). Anti-obesity compounds, Semaglutide and LiPR, and PrRP do not change the proportion of human and mouse POMC+ neurons.. PloS one, 20(8), e0329268. https://doi.org/10.1371/journal.pone.0329268