1. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling
- Author
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Mostafa Bakhti, Diego Perez-Tilve, Konxhe Kulaj, Beata Legutko, Susanna M. Hofmann, Dominik Lutter, Kerstin Stemmer, Gerd Luippold, Stephanie A. Mowery, Marta Tarquis Medina, Stephan Herzig, Gustav Collden, Robert Augustin, Timo D. Müller, Cristina Garcia Caceres, Christian Wolfrum, Richard D. DiMarchi, Susanne Keipert, Xue Liu, Qian Zhang, Alexandra Harger, Cassie Holleman, Brian Finan, Maximilian Kleinert, Emilija Malogajski, Ciro Salinno, Matthias H. Tschöp, Andreas Blutke, Martin Jastroch, Gerald Grandl, Annette Feuchtinger, Patrick J. Knerr, Daniel J. Drucker, Laura Sehrer, Challa Tenagne Delessa, and Heiko Lickert
- Subjects
0301 basic medicine ,Central Nervous System ,Male ,Food intake ,food intake ,Physiology ,Eating ,Mice ,0302 clinical medicine ,Glucagon-Like Peptide 1 ,Premovement neuronal activity ,2. Zero hunger ,GIP ,GIPR CNS KO ,incretin ,3. Good health ,Peripheral ,ddc ,Cns ,Gip ,Gipr Cns Ko ,Body Weight ,Diet-induced Obesity ,Food Intake ,Glucose Metabolism ,Incretin ,Type 2 Diabetes ,Metabolic effects ,Glucose-dependent insulinotropic polypeptide ,type 2 diabetes ,CNS ,Proto-Oncogene Proteins c-fos ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,medicine.medical_specialty ,diet-induced obesity ,glucose metabolism ,Hypothalamus ,Mice, Transgenic ,Gastric Inhibitory Polypeptide ,Biology ,Carbohydrate metabolism ,Body weight ,Diet, High-Fat ,Article ,Receptors, Gastrointestinal Hormone ,03 medical and health sciences ,body weight ,Internal medicine ,medicine ,Animals ,Humans ,ddc:610 ,Obesity ,Molecular Biology ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,030217 neurology & neurosurgery - Abstract
Summary 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., Graphical abstract, Highlights • 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.
- Published
- 2021