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Liskiewicz, A. ; Khalil, A. ; Liskiewicz, D. ; Novikoff, A. ; Grandl, G. ; Maity-Kumar, G. ; Gutgesell, R.M. ; Bakhti, M. ; Bastidas-Ponce, A. ; Czarnecki, O. ; Makris, K. ; Lickert, H. ; Feuchtinger, A. ; Tost, M. ; Coupland, C. ; Ständer, L. ; Akindehin, S.E. ; Prakash, S. ; Abrar, F. ; Castelino, R.L. ; He, Y.* ; Knerr, P.J.* ; Yang, B.* ; Hogendorf, W.F.J.* ; Zhang, S. ; Hofmann, S.M. ; Finan, B.* ; DiMarchi, R.D.* ; Tschöp, M.H. ; Douros, J.D.* ; Müller, T.D.

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

Nat. Metab. 5, 2075–2085 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
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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
Corresponding Author
Keywords Glp-1 Receptor Agonist; Gip
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Quellenangaben Volume: 5, Issue: , Pages: 2075–2085 Article Number: , Supplement: ,
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)
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.