The Glucose-Dependent Insulinotropic Polypeptide (GIP) Regulates Body Weight and Food Intake Via CNS-GIPR Signaling

Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. We show that HFD-fed CNS-Gipr ko mice and humanized (h)GIPR knock-in mice with CNS-hGIPR deletion show improved body weight and glycemia, but these metabolic improvements vanish upon adult-onset Gipr deletion. In DIO mice, acute central administration of acyl-GIP increases cFos neuronal activity in the arcuate, dorsomedial, paraventricular and lateral hypothalamus and leads to improved body weight, food intake, and glycemia. Chronic administration of acyl-GIP improves body weight and food intake in wildtype mice, but shows blunted/absent efficacy in CNS-Gipr ko mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 was extinguished in CNS-Gipr ko mice. Our data establish a key role of CNS Gipr for control of energy metabolism.