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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. 7, 1282–1298 (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
Keywords Glp-1 Receptor Agonist; Insulinotropic Polypeptide Gip; Gastric-inhibitory Polypeptide; Surrogate Indexes; Double-blind; Dual Gip; Tirzepatide; Expression; Resistance; Obesity
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Quellenangaben Volume: 7, Issue: , Pages: 1282–1298 Article Number: , Supplement: ,
Publisher Springer
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Computational Biology (ICB)
POF-Topic(s) 90000 - German Center for Diabetes Research
30201 - Metabolic Health
30205 - Bioengineering and Digital Health
Research field(s) Helmholtz Diabetes Center
Enabling and Novel Technologies
PSP Element(s) G-501900-221
G-502200-001
G-502296-001
G-502200-006
G-503800-001
G-501900-224
Grants German Center for Diabetes Research (DZD e.V.)
#101044445
European Union
Neither the European Union
German Research Foundation
DFG
European Research Council (ERC)
DOI 10.1038/s42255-025-01294-x
WOS ID 001478375300001
Scopus ID 105003832243
PubMed ID 40301583
Erfassungsdatum 2025-05-11
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