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

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.

• Authors: Qian Zhang, Challa Tenagne Delessa, Robert Augustin, Mostafa Bakhti, Gustav Colldén, Daniel J Drucker, Annette Feuchtinger, Cristina Garcia Caceres, Gerald Grandl, Alexandra Harger, Stephan Herzig, Susanna Hofmann, Cassie Lynn 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 Perez-Tilve, Ciro Salinno, Laura Sehrer, Richard D DiMarchi, Matthias H Tschöp, Kerstin Stemmer, Brian Finan, Christian Wolfrum, Timo D Müller
• Journal: Cell metabolism (Cell Metab) Vol. 33 Issue 4 Pg. 833-844.e5 (04 06 2021) ISSN: 1932-7420 [Electronic] United States
• PMID: 33571454 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Proto-Oncogene Proteins c-fos
• Receptors, Gastrointestinal Hormone
• Gastric Inhibitory Polypeptide
• Glucagon-Like Peptide 1
• gastric inhibitory polypeptide receptor

Topics

• Animals
• Body Weight (drug effects)
• Central Nervous System (metabolism)
• Diet, High-Fat
• Eating (drug effects)
• Gastric Inhibitory Polypeptide (chemistry, pharmacology)
• Glucagon-Like Peptide 1 (pharmacology)
• Humans
• Hypothalamus (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Obesity (metabolism, pathology, prevention & control)
• Proto-Oncogene Proteins c-fos (metabolism)
• Receptors, Gastrointestinal Hormone (deficiency, genetics, metabolism)
• Signal Transduction (drug effects)