The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling
Qian Zhang, Challa Tenagne Delessa, Robert Augustin, Mostafa Bakhti, Gustav Colldén, Daniel J. Drucker, Annette Feuchtinger, Cristina García Cáceres, Gerald Grandl, Alexandra Harger, Stephan Herzig, Susanna M. Hofmann, Cassie Holleman, Martin Jastroch, Susanne Keipert, Maximilian Kleinert, Patrick J. Knerr, Konxhe Kulaj, Beata Legutko, Heiko Lickert, Xue Liu, Gerd Luippold, Dominik Lutter, Emilija Malogajski, Marta Tarquis-Medina, Stephanie A. Mowery, Andreas Blutke, Diego Pérez–Tilve, Ciro Salinno, Laura Sehrer, Richard D. DiMarchi, Matthias H. Tschöp, Kerstin Stemmer, Brian Finan, Christian Wolfrum, Timo D. Müller
Abstract
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. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type 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 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism.