Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice

  • Nat Metab. 2023 Dec;5(12):2075-2085. doi: 10.1038/s42255-023-00931-7.
Arkadiusz Liskiewicz  1  2  3 ,  Ahmed Khalil  1  2 ,  Daniela Liskiewicz  1  2  4 ,  Aaron Novikoff  1  2 ,  Gerald Grandl  1  2 ,  Gandhari Maity-Kumar  1  2 ,  Robert M Gutgesell  1  2 ,  Mostafa Bakhti  2  5 ,  Aimée Bastidas-Ponce  2  5 ,  Oliver Czarnecki  2  5  6 ,  Konstantinos Makris  1  2 ,  Heiko Lickert  2  5  6 ,  Annette Feuchtinger  7 ,  Monica Tost  7 ,  Callum Coupland  1  2 ,  Lisa Ständer  1  2 ,  Seun Akindehin  1  2 ,  Sneha Prakash  1  2 ,  Faiyaz Abrar  1  2 ,  Russell L Castelino  1  2 ,  Yantao He  8 ,  Patrick J Knerr  8 ,  Bin Yang  8 ,  Wouter F J Hogendorf  8 ,  Shiqi Zhang  5 ,  Susanna M Hofmann  5  9 ,  Brian Finan  8 ,  Richard D DiMarchi  10 ,  Matthias H Tschöp  11  12 ,  Jonathan D Douros  8 ,  Timo D Müller  13  14
Affiliations
  • 1. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • 2. German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • 3. Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland.
  • 4. Institute of Physiotherapy and Health Sciences, Academy of Physical Education, Katowice, Poland.
  • 5. Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • 6. TUM School of Medicine, Technical University of Munich, Munich, Germany.
  • 7. Core Facility Pathology & Tissue Analytics, Helmholtz Munich, Neuherberg, Germany.
  • 8. Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
  • 9. Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany.
  • 10. Department of Chemistry, Indiana University, Bloomington, IN, USA.
  • 11. Helmholtz Munich, Neuherberg, Germany.
  • 12. Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany.
  • 13. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany. [email protected].
  • 14. German Center for Diabetes Research (DZD), Neuherberg, Germany. [email protected].
PMID: 37946085 DOI: 10.1038/s42255-023-00931-7
Abstract

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR-GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1-3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake3,6-8; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified. Here, we report that long-acting GIPR agonists and GIPR-GLP-1R co-agonists decrease body weight and food intake via inhibitory GABAergic neurons. We show that acyl-GIP decreases body weight and food intake in male diet-induced obese wild-type mice, but not in mice with deletion of Gipr in Vgat(also known as Slc32a1)-expressing GABAergic neurons (Vgat-Gipr knockout). Whereas the GIPR-GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake.

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