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

  • Cell Metab. 2021 Apr 6;33(4):833-844.e5. doi: 10.1016/j.cmet.2021.01.015.
Qian Zhang  1 ,  Challa Tenagne Delessa  2 ,  Robert Augustin  3 ,  Mostafa Bakhti  4 ,  Gustav Colldén  1 ,  Daniel J Drucker  5 ,  Annette Feuchtinger  6 ,  Cristina Garcia Caceres  1 ,  Gerald Grandl  1 ,  Alexandra Harger  1 ,  Stephan Herzig  7 ,  Susanna Hofmann  8 ,  Cassie Lynn Holleman  1 ,  Martin Jastroch  9 ,  Susanne Keipert  9 ,  Maximilian Kleinert  1 ,  Patrick J Knerr  10 ,  Konxhe Kulaj  1 ,  Beata Legutko  1 ,  Heiko Lickert  11 ,  Xue Liu  1 ,  Gerd Luippold  3 ,  Dominik Lutter  1 ,  Emilija Malogajski  1 ,  Marta Tarquis Medina  11 ,  Stephanie A Mowery  10 ,  Andreas Blutke  6 ,  Diego Perez-Tilve  12 ,  Ciro Salinno  11 ,  Laura Sehrer  1 ,  Richard D DiMarchi  13 ,  Matthias H Tschöp  14 ,  Kerstin Stemmer  1 ,  Brian Finan  10 ,  Christian Wolfrum  2 ,  Timo D Müller  15
Affiliations
  • 1. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • 2. Institute of Food, Nutrition and Health, Department of Health Sciences and Technology (D-HEST), ETH Zürich, Zurich, Switzerland.
  • 3. Cardiometabolic Diseases Research Department, Boehringer Ingelheim Pharma GmbH and Co., KG, Biberach/Riss, Germany.
  • 4. German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 5. Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
  • 6. Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 7. German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany; Molecular Metabolic Control, Technical University of Munich, Munich, Germany.
  • 8. German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der LMU, München, Germany.
  • 9. Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden.
  • 10. Novo Nordisk Research Center Indianapolis, Indianapolis, IN 46241, USA.
  • 11. German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, School of Medicine, Klinikum Rechts der Isar, 81675 München, Germany.
  • 12. Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 13. Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
  • 14. German Center for Diabetes Research (DZD), Neuherberg, Germany; Helmholtz Zentrum München, Neuherberg, Germany; Technische Universität München, München, Germany.
  • 15. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, 72076 Tübingen, Germany. Electronic address: [email protected].
PMID: 33571454 DOI: 10.1016/j.cmet.2021.01.015
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.

Keywords
CNS; GIP; GIPR CNS KO; body weight; diet-induced obesity; food intake; glucose metabolism; incretin; type 2 diabetes.
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