Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes

Publikation: Bidrag til tidsskrift › Letter › Forskning › fagfællebedømt

  • Jonathan D. Douros
  • Jette Bork-Jensen
  • Alessandro Berghella
  • Peter A. Gerlach
  • Jacek Mokrosiński
  • Stephanie A. Mowery
  • Patrick J. Knerr
  • Brian Finan
  • Jonathan E. Campbell
  • David A. D’Alessio
  • Diego Perez-Tilve
  • Henrik T. Sørensen
  • Allan Vaag
  • Jens S. Nielsen
  • Jeannet Lauenborg
  • Shane C. Wright
  • Volker M. Lauschke
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.
OriginalsprogEngelsk
TidsskriftNature Metabolism
ISSN2522-5812
DOI
StatusAccepteret/In press - 2024

Bibliografisk note

Funding Information:
This work was supported by a scholarship to H.S.K. from the Danish Diabetes Academy funded by the Novo Nordisk Foundation (grant no. NNF17SA0031406) and a grant to M.M.R. from the EFSD/Lilly European Diabetes Research Programme. M.M.R was also supported by a grant from the Novo Nordisk Foundation (grant no. NNF21OC0070347). K.V.S., J.B.-J., O.P., B.H., J.J.H., T.H. and N.G. were supported by an unrestricted grant (NNF18CC0034900 and NNF23SA0084103) donated by the Novo Nordisk Foundation to partly fund the independent research facility of the Novo Nordisk Foundation Center for Basic Metabolic Research. A.S.H. and J.S.M. gratefully acknowledge funding from the Lundbeck Foundation (R278-2018-180) and the Independent Research Fund Denmark (3122-00044B). A.V. was supported by The Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009-1039, and Swedish Foundation for Strategic Research, Dnr ICR15-0067. S.C.W. is supported by the Swedish Society for Medical Research (PD20-0153). V.M.L. is supported by the Swedish Research Council (grant agreement numbers 2019-01837 and 2021-02801), by the EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant number 875510) and by the Robert Bosch Foundation, Stuttgart, Germany.

Funding Information:
DD2 is supported by Danish Agency for Science (grant no. 09-067009 and 09-075724). DD2 is also supported by The Danish Health and Medicines Authority, The Danish Diabetes Association and an unrestricted donation from Novo Nordisk Foundation. The partners of the project are listed on the project website at www.DD2.nu . This research has been conducted using the UK Biobank Resource, a major biomedical database with genotype and phenotype data open to all approved health researchers ( https://www.ukbiobank.ac.uk/ ), under application number 55955. We thank A. Inoue (Tohoku University) for providing \u03B2-arrestin knockout cell lines; M. Bouvier (Universit\u00E9 de Montr\u00E9al) for rGFP-CAAX, rGFP-FYVE, tdrGFP-Giantin and tdrGFP-PTP1B; N.A. Lambert (Augusta University) for Rluc8-mGs; and M. Sigvardt Baggesen, S. Petersen, R. Regmi and A. Dragan for excellent technical assistance for the in vitro studies. Graphic illustrations were created with BioRender.com .

Publisher Copyright:
© The Author(s) 2024.

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