Identifying the Role of FGF Receptor 1 in AgRP Neurons to Regulate Energy and Glucose Homeostasis

Abstract

The arcuate nucleus of the hypothalamus (ARC) is an epicenter for metabolic regulation, housing neurons critical for interpreting afferent signals of energy status and delivering diverse efferent outputs to metabolically active tissues to regulate energy homeostasis. Within the ARC, Agouti-Related-Peptide-expressing (AgRP) neurons promote weight gain by triggering intense hunger and reducing energy expenditure. Importantly, overactivity of AgRP neurons is highly associated with increased food intake, weight gain, and elevated blood glucose levels. While previous investigations have indicated an important role for Fibroblast Growth Factor Receptor 1 (FGFR1) ligands in regulating metabolism via the central nervous system (CNS), the understanding of how this occurs remains incomplete. Therefore, the goals of this dissertation were to investigate the role of FGFR1 in AgRP neurons to regulate energy and glucose homeostasis and identify the underlying mechanisms by which this occurs. Similar to fibroblast growth factors (FGFs), central administration of [alpha]-Klotho, a scaffolding protein that aids in the binding of FGFs to FGFRs, elicits therapeutic effects in rodent models of type I and type II diabetes. While these effects were mediated by modulating AgRP neuron activity, the detailed mechanisms are not fully understood. Using targeted loss- and gain-of-function approaches to manipulate the expression of FGFR1 in AgRP neurons in adult mice, the data presented here shows that the deletion of FGFR1 in AgRP neurons alters energy homeostasis, favoring an obesogenic state, which is exacerbated when challenged with a high-fat diet (HFD). Furthermore, overexpression of FGFR1 in AgRP neurons mildly protects against obesity and improves glucose tolerance. Mechanistically, deletion of FGFR1 in AgRP neurons prevents [alpha]-Klotho mediated suppression of AgRP neuron activity, and mice lacking FGFR1 in AgRP neurons show elevated expression of the AgRP peptide, which is released as a neurotransmitter to elicit orexigenic effects. Providing further evidence of an [alpha]-Klotho-FGFR1-PI3K-FOXO1 signaling axis in AgRP neurons that acts similarly to leptin and insulin, regulating both the electrical properties and gene expression of the AgRP peptide. The work presented here identifies FGFR1 in AgRP neurons as a new therapeutic target to attempt to restore proper signaling in AgRP neurons in individuals with dysfunctional signaling or "resistance" to these metabolic factors and shows that FGFR1 in AgRP neurons is an integral component of regulating glucose and energy homeostasis.