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.