Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes
(2024) In Nature Metabolism 6(7). p.1268-1281- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2024-07
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Metabolism
- volume
- 6
- issue
- 7
- pages
- 14 pages
- publisher
- Springer Nature
- external identifiers
-
- scopus:85196101926
- pmid:38871982
- ISSN
- 2522-5812
- DOI
- 10.1038/s42255-024-01061-4
- language
- English
- LU publication?
- yes
- id
- 21b7dcd9-415b-4175-865d-eb3b1a6aeed4
- date added to LUP
- 2024-09-04 15:28:27
- date last changed
- 2024-09-05 03:00:05
@article{21b7dcd9-415b-4175-865d-eb3b1a6aeed4,
abstract = {{<p>Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes<sup>1</sup>. 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 tirzepatide<sup>2</sup> and AMG-133 (ref. <sup>3</sup>) 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>}},
author = {{Kizilkaya, Hüsün S. and Sørensen, Kimmie V. and Madsen, Jakob S. and Lindquist, Peter and Douros, Jonathan D. and Bork-Jensen, Jette and Berghella, Alessandro and Gerlach, Peter A. and Gasbjerg, Lærke S. and Mokrosiński, Jacek and Mowery, Stephanie A. and Knerr, Patrick J. and Finan, Brian and Campbell, Jonathan E. and D’Alessio, David A. and Perez-Tilve, Diego and Faas, Felix and Mathiasen, Signe and Rungby, Jørgen and Sørensen, Henrik T. and Vaag, Allan and Nielsen, Jens S. and Holm, Jens Christian and Lauenborg, Jeannet and Damm, Peter and Pedersen, Oluf and Linneberg, Allan and Hartmann, Bolette and Holst, Jens J. and Hansen, Torben and Wright, Shane C. and Lauschke, Volker M. and Grarup, Niels and Hauser, Alexander S. and Rosenkilde, Mette M.}},
issn = {{2522-5812}},
language = {{eng}},
number = {{7}},
pages = {{1268--1281}},
publisher = {{Springer Nature}},
series = {{Nature Metabolism}},
title = {{Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes}},
url = {{http://dx.doi.org/10.1038/s42255-024-01061-4}},
doi = {{10.1038/s42255-024-01061-4}},
volume = {{6}},
year = {{2024}},
}