CRISPR/Cas9-Mediated Deletion of FGF Receptor 1 in AgRP Neurons Results in Obesity and Impaired Glucose Metabolism

Obesity remains a growing epidemic as current treatment approaches have limited success. We have recently identified hypothalamic α-Klotho as a novel metabolic regulator; however, the downstream pathways remain unclear. Using a Cre-dependent CRISPR/Cas9 system alongside transgenic mice to investigate the role of FGFR1 in defined neuron populations of adult mice, we show that deletion of FGFR1 in AgRP neurons results in increased weight gain and adiposity, worsened glucose tolerance, and increased liver lipid accumulation. Mechanistically, deletion of FGFR1 negates pERK signaling and the ability of α-Klotho to reduce fasting-induced AgRP neuron activity in mice. While in hypothalamic cells, knockdown of FGFR1 prevents FOXO1 phosphorylation by α-Klotho, providing evidence of an α-Klotho-FGFR1-PI3K-FOXO1 signaling axis in AgRP neurons. Taken together, our data demonstrate the metabolic role of FGFR1 in AgRP neurons and identify it as a critical regulator of energy and glucose homeostasis. Disclosure D. Shookster: None. H. Huang: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK121215 to H.H.)