GLP1R agonists activate human POMC neurons

doi:10.1101/2024.04.02.587825

Paper

GLP1R agonists activate human POMC neurons

Published Apr 3, 2024 · Simone Mazzaferro, Hsiao-Jou Cortina Chen, Oliver Cahn

bioRxiv

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Abstract

Drugs like Semaglutide (a.k.a. Ozempic/Wegovy) that activate the glucagon-like peptide-1 receptor (GLP1R) are a promising therapy for obesity and type 2 diabetes (T2D). Animal studies suggest that appetite-suppressing proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus are a likely target of these drugs, but the mechanisms by which they reduce food intake in humans are still unclear. We therefore generated POMC neurons from human pluripotent stem cells (hPSCs) to study their acute responses to GLP1R agonists by calcium imaging and electrophysiology. We found that hPSC-derived POMC neurons expressed GLP1R and many of them robustly responded to GLP1R agonists by membrane depolarization, increased action potential firing rate, and extracellular calcium influx that persisted long after agonist withdrawal and was likely mediated by L-type calcium channels. Prolonged administration of Semaglutide upregulated transcriptional pathways associated with cell survival in POMC neurons, and downregulated pathways associated with oxidative stress and neurodegeneration. These findings suggest that POMC neurons contribute to the long-term appetite-suppressive effects of GLP1R agonists in humans.

In Vitro Study

Preprint

Study Snapshot

GLP1R agonists activate human POMC neurons, contributing to their long-term appetite-suppressive effects in obesity and type 2 diabetes patients.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

GLP1R agonists activate human POMC neurons

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