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Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice.
Nat. Metab. 5, 2075–2085 (2023)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Glp-1 Receptor Agonist; Gip
ISSN (print) / ISBN
2522-5812
e-ISSN
2522-5812
Journal
Nature metabolism
Quellenangaben
Volume: 5,
Pages: 2075–2085
Publisher
Springer
Publishing Place
London
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes and Obesity (IDO)
Institute of Diabetes and Regeneration Research (IDR)
CF Pathology & Tissue Analytics (CF-PTA)
Institute of Diabetes and Regeneration Research (IDR)
CF Pathology & Tissue Analytics (CF-PTA)
Grants
European Research Council
German Center for Diabetes Research
German Research Foundation
European Research Council ERC-CoG Trusted
T.D.M. received funding for this work from the European Research Council ERC-CoG Trusted no. 101044445. T.D.M. also received funding from the German Research Foundation (TRR296, TRR152, SFB1123 and GRK 2816/1) and the German Center for Diabetes Research.
German Center for Diabetes Research
German Research Foundation
European Research Council ERC-CoG Trusted
T.D.M. received funding for this work from the European Research Council ERC-CoG Trusted no. 101044445. T.D.M. also received funding from the German Research Foundation (TRR296, TRR152, SFB1123 and GRK 2816/1) and the German Center for Diabetes Research.