FGFR1 Signaling in AgRP Neurons for Regulating Metabolism - PROJECT ABSTRACT The long-term objective of this proposal is to determine the physiological role of hypothalamic FGFR1 in metabolic regulation, establish a previously uncovered signaling pathway of FGFR1-PI3K-FOXO1 in AgRP neurons that contributes to neuronal activity associated with obesity and its related diseases. We have previously reported that α-klotho, a known anti-aging protein, is a novel humoral factor that targets hypothalamic AgRP neurons, which regulate energy and blood glucose metabolism. Furthermore, inhibition of FGFR1 abolished the downstream signaling of α-klotho, negated its ability to modulate AgRP neuron activity, and blunted its therapeutic effects, suggesting an important central FGFR1 mediated signaling. However, conventional selective genetic deletion of FGFR1 in AgRP neurons has previously failed to produce a notable metabolic phenotype, which may be due to potential compensatory effects induced by the absence of FGFR1 during development. Based on this discrepancy, the overall goal of this project is to determine whether FGFR1 signaling in mature AgRP neurons is required for the homeostatic regulation of energy balance. The proposed studies will utilize selectively targeted loss- and gain-of-function approaches (AAV/CRISPR/CAS9) and mouse models of obesity and diabetes to identify the neuronal and molecular mechanisms underlying FGFR1 metabolic effects.
