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Plate IV.93 · Publications

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

Article in Nature Metabolism, 29 April 2025.

Open accessBrain, Neurons, Reprogramming

  1. Robert M. Gutgesell
  2. Ahmed Khalil
  3. Arkadiusz Liskiewicz
  4. Gandhari Maity-Kumar
  5. Aaron Novikoff
  6. Gerald Grandl
  7. Daniela Liskiewicz
  8. Callum Coupland
  9. Ezgi Karaoglu
  10. Seun Akindehin
  11. Russell Castelino
  12. Fabiola Curion
  13. Xue Liu
  14. Cristina Garcia-Caceres
  15. Alberto Cebrian-Serrano
  16. Jonathan D. Douros
  17. Patrick J. Knerr
  18. Brian Finan
  19. Richard D. DiMarchi
  20. Kyle W. Sloop
  21. Ricardo J. Samms
  22. Fabian J. Theis
  23. Matthias H. Tschöp
  24. Timo D. Müller

Abstract

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.

Versions2

  1. CorrectionNature Metabolism10.1038/s42255-025-01308-8
  2. PublishedNature Metabolism10.1038/s42255-025-01294-x

Cite

@article{gutgesell2025gipr,
  title = {{GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice}},
  author = {Gutgesell, Robert M. and Khalil, Ahmed and Liskiewicz, Arkadiusz and Maity-Kumar, Gandhari and Novikoff, Aaron and Grandl, Gerald and Liskiewicz, Daniela and Coupland, Callum and Karaoglu, Ezgi and Akindehin, Seun and Castelino, Russell and Curion, Fabiola and Liu, Xue and Garcia-Caceres, Cristina and Cebrian-Serrano, Alberto and Douros, Jonathan D. and Knerr, Patrick J. and Finan, Brian and DiMarchi, Richard D. and Sloop, Kyle W. and Samms, Ricardo J. and Theis, Fabian J. and Tschöp, Matthias H. and Müller, Timo D.},
  journal = {Nature Metabolism},
  publisher = {Springer Science and Business Media LLC},
  year = {2025},
  month = apr,
  doi = {10.1038/s42255-025-01294-x},
  url = {https://doi.org/10.1038/s42255-025-01294-x},
  pmid = {40301583},
  pmcid = {PMC12198009}
}
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