GLP1R agonists activate human POMC neurons

Mazzaferro, S.; Chen, H.-J. C.; Cahn, O.; Yang, A.; Shepilov, D.; Chen, J.; Alcaino, C.; Macarelli, V.; Mali, I.; Gribble, F.; Reimann, F.; Marioni, J.; Merkle, F. T.

doi:10.1101/2024.04.02.587825

bioRxiv · 10.1101/2024.04.02.587825

GLP1R agonists activate human POMC neurons

Mazzaferro, S.·Chen, H.-J. C.·Cahn, O.·Yang, A.·Shepilov, D.·Chen, J.·Alcaino, C.·Macarelli, V.·Mali, I.·Gribble, F.·Reimann, F.·Marioni, J.·Merkle, F. T.

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Abstract

Drugs like semaglutide (a.k.a. Ozempic/Wegovy) that activate the glucagon-like peptide-1 receptor (GLP-1R) are a promising therapy for obesity and type 2 diabetes (T2D). Animal studies suggest that these drugs likely function by stimulating GLP-1R on appetite-suppressing neuron populations in the brain, but it is still unclear how they act to reduce food intake in humans. We therefore generated appetite-regulatory hypothalamic neurons from human pluripotent stem cells (hPSCs) to study their responses to GLP-1R agonists by calcium imaging and electrophysiology. We found that hPSC-derived proopiomelanocortin (POMC) and other hypothalamic neuron subtypes expressed GLP1R mRNA, and many of these neurons robustly responded to GLP-1R agonists by membrane depolarization, increased action potential firing, and extracellular calcium influx that persisted long after agonist withdrawal. The observed GLP-1R-induced response was likely mediated by the activation of PKA and L-type calcium channels, and led to significant changes in gene expression. These findings provide mechanistic insight into how GLP-1R agonists may suppress appetite in humans.

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Mazzaferro, S., Chen, H.-J. C., Cahn, O., Yang, A., Shepilov, D., Chen, J., Alcaino, C., Macarelli, V., Mali, I., Gribble, F., Reimann, F., Marioni, J., Merkle, F. T.. 2024-04-03. GLP1R agonists activate human POMC neurons. https://doi.org/10.1101/2024.04.02.587825

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