The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling

• Published in: Cell metabolism Vol. 33; no. 4; pp. 833 - 844.e5
• Main Authors: Zhang, Qian, Delessa, Challa Tenagne, Augustin, Robert, Bakhti, Mostafa, Colldén, Gustav, Drucker, Daniel J., Feuchtinger, Annette, Caceres, Cristina Garcia, Grandl, Gerald, Harger, Alexandra, Herzig, Stephan, Hofmann, Susanna, Holleman, Cassie Lynn, Jastroch, Martin, Keipert, Susanne, Kleinert, Maximilian, Knerr, Patrick J., Kulaj, Konxhe, Legutko, Beata, Lickert, Heiko, Liu, Xue, Luippold, Gerd, Lutter, Dominik, Malogajski, Emilija, Medina, Marta Tarquis, Mowery, Stephanie A., Blutke, Andreas, Perez-Tilve, Diego, Salinno, Ciro, Sehrer, Laura, DiMarchi, Richard D., Tschöp, Matthias H., Stemmer, Kerstin, Finan, Brian, Wolfrum, Christian, Müller, Timo D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.04.2021; Cell Press
• Subjects: Animals; body weight; Body Weight - drug effects; Central Nervous System - metabolism; CNS; Diet, High-Fat; diet-induced obesity; Eating - drug effects; food intake; Gastric Inhibitory Polypeptide - chemistry; Gastric Inhibitory Polypeptide - pharmacology; GIP; GIPR CNS KO; Glucagon-Like Peptide 1 - pharmacology; glucose metabolism; Humans; Hypothalamus - metabolism; incretin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity - metabolism; Obesity - pathology; Obesity - prevention & control; Proto-Oncogene Proteins c-fos - metabolism; Receptors, Gastrointestinal Hormone - deficiency; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - metabolism; Signal Transduction - drug effects; type 2 diabetes; body weight; type 2 diabetes; incretin; GIPR CNS KO; CNS; glucose metabolism; diet-induced obesity; GIP; food intake
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2021.01.015

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. [Display omitted] •CNS-Gipr KO mice are protected from diet-induced obesity and glucose intolerance•Acyl-GIP increases cFOS neuronal activity in key hypothalamic feeding centers•Acyl-GIP effects on body weight and food intake are absent/blunted in CNS-mGipr KO mice•GLP-1/GIP dual-agonism loses superior potency over GLP-1 in CNS-mGipr KO mice. Zhang et al. report that CNS GIPR plays a significant role in regulating food intake. They show that treatment with acyl-GIP or with a GLP-1/GIP dual-agonist lowers body weight and food intake in wild-type mice but shows blunted efficacy in CNS-Gipr KO mice.