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Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice.
Liskiewicz, Arkadiusz; Khalil, Ahmed; Liskiewicz, Daniela; Novikoff, Aaron; Grandl, Gerald; Maity-Kumar, Gandhari; Gutgesell, Robert M; Bakhti, Mostafa; Bastidas-Ponce, Aimée; Czarnecki, Oliver; Makris, Konstantinos; Lickert, Heiko; Feuchtinger, Annette; Tost, Monica; Coupland, Callum; Ständer, Lisa; Akindehin, Seun; Prakash, Sneha; Abrar, Faiyaz; Castelino, Russell L; He, Yantao; Knerr, Patrick J; Yang, Bin; Hogendorf, Wouter F J; Zhang, Shiqi; Hofmann, Susanna M; Finan, Brian; DiMarchi, Richard D; Tschöp, Matthias H; Douros, Jonathan D; Müller, Timo D.
Affiliation
  • Liskiewicz A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • Khalil A; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Liskiewicz D; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland.
  • Novikoff A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • Grandl G; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Maity-Kumar G; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • Gutgesell RM; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Bakhti M; Institute of Physiotherapy and Health Sciences, Academy of Physical Education, Katowice, Poland.
  • Bastidas-Ponce A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • Czarnecki O; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Makris K; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • Lickert H; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Feuchtinger A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • Tost M; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Coupland C; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • Ständer L; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Akindehin S; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Prakash S; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • Abrar F; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Castelino RL; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • He Y; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Knerr PJ; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • Yang B; TUM School of Medicine, Technical University of Munich, Munich, Germany.
  • Hogendorf WFJ; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
  • Zhang S; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Hofmann SM; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Finan B; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • DiMarchi RD; TUM School of Medicine, Technical University of Munich, Munich, Germany.
  • Tschöp MH; Core Facility Pathology & Tissue Analytics, Helmholtz Munich, Neuherberg, Germany.
  • Douros JD; Core Facility Pathology & Tissue Analytics, Helmholtz Munich, Neuherberg, Germany.
  • Müller TD; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
Nat Metab ; 5(12): 2075-2085, 2023 Dec.
Article in En | MEDLINE | ID: mdl-37946085
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Diabetes Mellitus, Type 2 Limits: Animals Language: En Journal: Nat Metab Year: 2023 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Diabetes Mellitus, Type 2 Limits: Animals Language: En Journal: Nat Metab Year: 2023 Document type: Article Affiliation country: