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Gutgesell, R.M. ; Khalil, A. ; Liskiewicz, A. ; Maity-Kumar, G. ; Novikoff, A. ; Grandl, G. ; Liskiewicz, D. ; Coupland, C. ; Karaoglu, Ö.E. ; Akindehin, S.E. ; Castelino, R.L. ; Curion, F. ; Liu, X. ; García-Cáceres, C. ; Cebrian Serrano, A. ; Douros, J.D.* ; Knerr, P.J.* ; Finan, B.* ; DiMarchi, R.D.* ; Sloop, K.W.* ; Samms, R.J.* ; Theis, F.J. ; Tschöp, M.H. ; Müller, T.D.

GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice.

Nat. Metab., DOI: 10.1038/s42255-025-01294-x (2025)
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Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Glp-1 Receptor Agonist; Insulinotropic Polypeptide Gip; Gastric-inhibitory Polypeptide; Surrogate Indexes; Double-blind; Dual Gip; Tirzepatide; Expression; Resistance; Obesity
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Publisher Springer
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Computational Biology (ICB)
Grants German Center for Diabetes Research (DZD e.V.)
#101044445
European Union
Neither the European Union
German Research Foundation
DFG
European Research Council (ERC)