GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice
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<sup>+</sup> 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.
Authors
- Matthias Tschoep (ORCID: https://orcid.org/0000-0002-4744-371X)
- Jonathan D. Douros (ORCID: https://orcid.org/0000-0003-2299-6163)
- Fabiola Curion (ORCID: https://orcid.org/0000-0003-2502-8803)
- Daniela Liśkiewicz (ORCID: https://orcid.org/0000-0002-5859-6316)
- Callum Coupland (ORCID: https://orcid.org/0000-0001-8921-3616)
- Patrick J. Knerr
- Gandhari Maity‐Kumar
- Robert M. Gutgesell (ORCID: https://orcid.org/0000-0001-6137-0468)
- Aaron Novikoff (ORCID: https://orcid.org/0000-0002-4838-001X)
- Arkadiusz Liśkiewicz (ORCID: https://orcid.org/0000-0002-4102-5373)
- Brian Finan (ORCID: https://orcid.org/0000-0002-6467-0447)
- Timo D. Müller (ORCID: https://orcid.org/0000-0002-0624-9339)
- Ahmed Khalil (ORCID: https://orcid.org/0009-0000-2204-8636)
- Cristina García‐Cáceres (ORCID: https://orcid.org/0000-0001-6376-9448)
- Ricardo J. Samms (ORCID: https://orcid.org/0000-0001-9138-3091)
- R.L. Castelino (ORCID: https://orcid.org/0009-0008-7446-6299)
- Kyle W. Sloop (ORCID: https://orcid.org/0000-0001-6748-9929)
- Richard D. DiMarchi (ORCID: https://orcid.org/0000-0003-0220-4085)
- Seun Akindehin (ORCID: https://orcid.org/0000-0002-6557-0843)
- Fabian Joachim Theis (ORCID: https://orcid.org/0000-0002-2419-1943)
- Gerald Grandl (ORCID: https://orcid.org/0000-0003-4456-1988)
- Alberto Cebrian-Serrano (ORCID: https://orcid.org/0000-0002-4737-0215)
- Xue Liu (ORCID: https://orcid.org/0000-0002-9588-5491)
- Ezgi Karaoglu
Institutions
- Medical University of Silesia (PL)
- Eli Lilly (United States) (US)
- Indiana Biosciences Research Institute (US)
- Helmholtz Zentrum München (DE)
- LMU Klinikum (DE)
- Indiana University Bloomington (US)
- Centre of Experimental Medicine of the Slovak Academy of Sciences (SK)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- Heinrich Heine University Düsseldorf (DE)
- Technical University of Munich (DE)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1038/s42255-025-01294-x
- Citations
- 22
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 17.73
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Helmholtz Zentrum München