Selective deletion of FGFR1 in AgRP neurons impairs energy homeostasis under high-fat diet in mice

The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined. To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models. Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 loss increased the intrinsic firing rate of AgRP neurons and abolished the suppressive effect of α-Klotho on their activity. At the molecular level, FGFR1 knockdown decreased phosphorylation of the transcription factor FOXO1 and elevated AgRP mRNA expression. Our results define a crucial FGFR1 signaling axis in AgRP neurons that coordinately regulates their electrical activity and peptide expression, thereby establishing FGFR1 as an essential regulator of energy homeostasis. Proposed mechanisms by which FGFR1 regulates AgRP neuron activity and FOXO1 phosphorylation in the hypothalamic cell line • Selective FGFR1 deletion in adult mouse AgRP neurons, achieved via an AAV-mediated Cre-dependent CRISPR-Cas9 system, reveals its critical post-developmental role in energy homeostasis. • Deletion of FGFR1 in AgRP neurons disrupts energy homeostasis, leading to increased weight gain, an effect induced by a high-fat diet. • FGFR1 is essential for regulating AgRP neuron excitability, as its loss increases firing rates and abolishes the suppressive effect of α-Klotho. • At the molecular level, FGFR1 knockdown decreases FOXO1 phosphorylation and increases AgRP mRNA. • We identify the FGFR1 signaling that coordinately controls the electrical activity and gene expression of AgRP neurons to regulate body weight.