GLP-1R agonists activate human hypothalamic neurons

Simone Mazzaferro; Hsiao‐Jou Cortina Chen; Olivier Cahn; Andrian Yang; Dmytro Shepilov; Eugene Seah; Jiahui Chen; Bavesh Jawahar; Constanza Alcaino; Viviana Macarelli; Iman D. Mali; John A. Tadross; Fiona Mary Gribble; Frank M. Reimann; John C. Marioni; Florian T. Merkle

doi:10.1101/2024.04.02.587825

NeurosciencebioRxivApr 2, 2024

Preprint

GLP-1R agonists activate human hypothalamic neurons

Simone Mazzaferro iD, Hsiao‐Jou Cortina Chen iD, Olivier Cahn, Andrian Yang iD, Dmytro Shepilov iD, Eugene Seah, Jiahui Chen iD, Bavesh Jawahar, Constanza Alcaino iD, Viviana Macarelli iD, Iman D. Mali iD, John A. Tadross iD, Fiona Mary Gribble iD, Frank M. Reimann iD, John C. Marioni iD, Florian T. Merkle iD

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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