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

Autor: Liskiewicz A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland., Khalil A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Liskiewicz D; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Institute of Physiotherapy and Health Sciences, Academy of Physical Education, Katowice, Poland., Novikoff A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Grandl G; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Maity-Kumar G; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Gutgesell RM; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Bakhti M; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany., Bastidas-Ponce A; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany., Czarnecki O; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.; TUM School of Medicine, Technical University of Munich, Munich, Germany., Makris K; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Lickert H; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.; TUM School of Medicine, Technical University of Munich, Munich, Germany., Feuchtinger A; Core Facility Pathology & Tissue Analytics, Helmholtz Munich, Neuherberg, Germany., Tost M; Core Facility Pathology & Tissue Analytics, Helmholtz Munich, Neuherberg, Germany., Coupland C; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Ständer L; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Akindehin S; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Prakash S; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Abrar F; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Castelino RL; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., He Y; Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA., Knerr PJ; Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA., Yang B; Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA., Hogendorf WFJ; Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA., Zhang S; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany., Hofmann SM; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.; Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany., Finan B; Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA., DiMarchi RD; Department of Chemistry, Indiana University, Bloomington, IN, USA., Tschöp MH; Helmholtz Munich, Neuherberg, Germany.; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany., Douros JD; Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA., Müller TD; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany. timodirk.mueller@helmholtz-munich.de.; German Center for Diabetes Research (DZD), Neuherberg, Germany. timodirk.mueller@helmholtz-munich.de.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2023 Dec; Vol. 5 (12), pp. 2075-2085. Date of Electronic Publication: 2023 Nov 09.
DOI: 10.1038/s42255-023-00931-7
Abstrakt: 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 preclinical 1-3 and clinical studies 4,5 , 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 intake 3,6-8 ; 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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