| Title: | Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes |
| Journal: | Nature Metabolism |
| Published: | 13 Jun 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38871982/ |
| DOI: | https://doi.org/10.1038/s42255-024-01061-4 |
| URL: | https://www.nature.com/articles/s42255-024-01061-4.pdf |
Publication 11863
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Abstract
Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.</p>
35 Authors
- Hüsün S. Kizilkaya
- Kimmie V. Sørensen
- Jakob S. Madsen
- Peter Lindquist
- Jonathan D. Douros
- Jette Bork-Jensen
- Alessandro Berghella
- Peter A. Gerlach
- Lærke S. Gasbjerg
- Jacek Mokrosiński
- Stephanie A. Mowery
- Patrick J. Knerr
- Brian Finan
- Jonathan E. Campbell
- David A. D'Alessio
- Diego Perez-Tilve
- Felix Faas
- Signe Mathiasen
- Jørgen Rungby
- Henrik T. Sørensen
- Allan Vaag
- Jens S. Nielsen
- Jens-Christian Holm
- Jeannet Lauenborg
- Peter Damm
- Oluf Pedersen
- Allan Linneberg
- Bolette Hartmann
- Jens J. Holst
- Torben Hansen
- Shane C. Wright
- Volker M. Lauschke
- Niels Grarup
- Alexander S. Hauser
- Mette M. Rosenkilde
1 Application
| Application ID | Title |
|---|---|
| 55955 | Advancing personalised medicine for psychiatric diseases through integrative GPCR pharmacogenomics |
Enabling scientific discoveries that improve human health