Overexpression of FGFR1 in AgRP neurons protects against obesity and improves glucose homeostasis.

BACKGROUND: The rising prevalence of metabolic disorders highlights the need to identify targetable pathways. Although hypothalamic AgRP neuron signaling influences energy balance, the beneficial role of fibroblast growth factor receptor 1 (FGFR1) within these neurons remains incompletely understood. METHODS: We employed an AAV-mediated CRISPR/Cas9 activation system to achieve AgRP neuron-specific overexpression of FGFR1 in adult mice. Metabolic phenotypes were assessed during high-fat diet (HFD) feeding, and mechanistic insights were gained using GT1-7 hypothalamic cells. RESULTS: FGFR1 overexpression in AgRP neurons attenuated high-fat diet (HFD)-induced weight gain and improved glucose tolerance, effects that were associated with reduced energy intake. Mechanistically, FGFR1 overexpression correlated with increased FOXO1 phosphorylation and reduced AgRP mRNA expression, suggesting a potential FGFR1-FOXO1 regulatory axis. CONCLUSION: These findings identify a contributory role for AgRP neuronal FGFR1 signaling in modulating metabolic outcomes under HFD conditions and suggest that this pathway may represent a potential avenue for further investigation in the context of obesity and diabetes.