FoxO1 Target Gpr17 Activates AgRP Neurons to Regulate Food Intake

Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity. [Display omitted] ► FoxO1 knockout in AgRP neurons mimics insulin and leptin action ► FoxO1-deficient AgRP mice are lean and have reduced food intake ► Gpr17 is a FoxO1 target, and its expression promotes food intake ► Agonists of Gpr17 increase food intake, whereas antagonists curtail it AgRP neurons respond to leptin and insulin, regulating food intake via FoxO1 signaling. Antagonists of a newly identified FoxO1 target, GPR17, promote satiety in mice, which suggests that this pathway can be targeted to treat obesity.