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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)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Glp-1 Receptor Agonist; Gip
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Zeitschrift Nature metabolism
Quellenangaben Band: 5, Heft: , Seiten: 2075–2085 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Institute of Diabetes and Regeneration Research (IDR)
CF Pathology & Tissue Analytics (CF-PTA)
Förderungen 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.