Through a combination of pharmacological, mouse genetic, and brain explant studies, we demonstrated that the gut-derived incretin hormone glucose-dependent insulinotropic polypeptide, also known as gastric inhibitory polypeptide (GIP), acted on the hypothalamic metabolic circuitry to drive leptin and insulin resistance as well as obesity by activating Epac-Rap1 signaling10,11. This evidence concerns the gene RAPGEF4 and obesity due to melanocortin 4 receptor deficiency.