Cahn, O. | Search bioRxiv

bioRxiv2024

GLP1R agonists activate human POMC neurons

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.

neuroscience↗

bioRxiv2023

Profiling human hypothalamic neurons reveals a candidate combination drug therapy for weight loss

Obesity substantially increases the risk of type 2 diabetes, cardiovascular disease, and other diseases, making it a leading preventable cause of death in developed countries. It has a strong genetic basis, with obesity-associated genetic variants preferentially acting in the brain. This includes the hypothalamic pro-opiomelanocortin (POMC) neurons that inhibit food intake and are stimulated by drugs that agonise glucagon-like 1 peptide receptor (GLP1R) including Semaglutide (Ozempic/Wegovy). We therefore hypothesised that drugs which selectively activate human POMC neurons would suppress appetite and promote weight loss, and that focusing on drugs already approved for use would facilitate rapid clinical translation. We therefore generated POMC neurons from human pluripotent stem cells (hPSCs) and identified enriched genes that were genetically associated with obesity and targeted by approved drugs. We found that human POMC neurons are enriched in GLP1R, reliably activated by Semaglutide, and their responses are further increased by co-administration of Ceritinib, an FDA-approved drug potently and selectively inhibiting anaplastic lymphoma kinase (ALK). Ceritinib reduced food intake and body weight in obese but not lean mice, and upregulated the expression of GLP1R in the mouse hypothalamus and hPSC-derived human hypothalamic neurons. These studies reveal a new potential therapeutic strategy for reducing food intake and body weight, and demonstrate the utility of hPSC-derived hypothalamic neurons for drug discovery.

neuroscience↗