Abstract
The incretin receptor agonists semaglutide and tirzepatide have transformed the medical management of obesity. The neural mechanisms by which incretin analogs regulate appetite remain incompletely understood, and dissecting this process is critical for the development of next-generation antiobesity drugs that are more targeted and tolerable. Moreover, the physiologic functions of incretins in appetite regulation and gut-brain communication have remained elusive. Using in vivo fiber photometry, we discovered distinct pharmacologic and physiologic roles for the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We showed that GIP, but not GLP-1, was required for normal nutrient-mediated inhibition of hunger-promoting AgRP neurons. By contrast, both GIP and GLP-1 analogs at pharmacologic doses were sufficient to inhibit AgRP neurons. The magnitude of neural inhibition was proportional to the effect of each incretin on food intake, and dual GIP and GLP-1 receptor agonism more potently inhibited AgRP neurons and suppressed food intake than either agonist alone. Our results have revealed a role for endogenous GIP in gut-brain appetite regulation and indicate that incretin analogs act in part via AgRP neurons to mediate their anorectic effects.