Deletion of FGFR1 in hypothalamic neurons alters energy homeostasis and negates the metabolic effects of α-Klotho.

BACKGROUND: The global obesity epidemic necessitates the identification of novel therapeutic targets. Although central administration of α-Klotho improves metabolic function in rodents, its precise mechanisms of action remain unclear. Since α-Klotho signals through fibroblast growth factor receptors (FGFRs), we hypothesized that FGFR1 within specific hypothalamic neuronal populations is critical for maintaining metabolic homeostasis. METHODS: We investigated the metabolic role of FGFR1 in the arcuate nucleus of adult mice using an adeno-associated virus (AAV)-mediated CRISPR/Cas9 system, in conjunction with transgenic models, to achieve cell-type-specific knockout of FGFR1 in mature glutamatergic, gamma-aminobutyric acid (GABA)ergic, and agouti-related peptide (AgRP) neurons. RESULTS: We found that FGFR1 governs distinct metabolic functions in different neuronal populations. Conditional deletion of FGFR1 in glutamatergic neurons impaired glucose tolerance. In contrast, its ablation in GABAergic neurons induced a severe energy imbalance, resulting in obesity characterized by significant weight gain and adiposity. Notably, AgRP neuron-specific deletion of FGFR1 recapitulated this obese phenotype. Furthermore, the loss of FGFR1 in AgRP neurons disrupted α-Klotho signaling, preventing its ability to modulate AgRP neuron activity and abolishing its beneficial effects on glucose and energy metabolism. CONCLUSION: Our results establish FGFR1 in hypothalamic neurons as an essential component of the pathway through which α-Klotho regulates systemic energy balance. These findings identify hypothalamic FGFR1 as a critical molecular target for developing anti-obesity therapies.