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

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作   者：

Kizilkaya, Husun S.;  Sorensen, Kimmie V.;  Madsen, Jakob S.;  Lindquist, Peter;  Douros, Jonathan D.;  Bork-Jensen, Jette;  Berghella, Alessandro;  Gerlach, Peter A.;  Gasbjerg, Laerke S.;  Mokrosinski, Jacek;  Mowery, Stephanie A.;  Knerr, Patrick J.;  Finan, Brian;  Campbell, Jonathan E.;  D'Alessio, David A.;  Perez-Tilve, Diego;  Faas, Felix;  Mathiasen, Signe;  Rungby, Jorgen;  Sorensen, Henrik T.;  Vaag, Allan;  Nielsen, Jens S.;  Holm, Jens-Christian;  Lauenborg, Jeannet;  Damm, Peter;  Pedersen, Oluf;  Linneberg, Allan;  Hartmann, Bolette;  Holst, Jens J.;  Hansen, Torben;  Wright, Shane C.;  Lauschke, Volker M.;  Grarup, Niels;  Hauser, Alexander S.;  Rosenkilde, Mette M.; 

作者机构：

University of Copenhagen Department of Drug Design and Pharmacology;  Duke Univ Durham;  Steno Diabet Ctr Copenhagen;  University of Copenhagen Department of Biomedical Sciences;  Copenhagen Univ Hosp Herlev;  Odense Univ Hosp;  Aarhus University Department of Clinical Epidemiology;  Novo Nordisk Res Ctr Indianapolis;  University of Cincinnati College of Medicine;  Karolinska Institute Department of Physiology and Pharmacology;  University of Copenhagen Faculty of Health and Medical Sciences; 

关键词：

OBESE CHILDREN;  UK BIOBANK;  FRAMEWORK;  RECEPTOR;  GASTRIC-INHIBITORY POLYPEPTIDE;  INSULIN SENSITIVITY;  ASSOCIATION;  GLUCOSE-TOLERANCE;  DISCOVERY;  PATHOPHYSIOLOGY; 

期刊名称：

Nature Metabolism

i s s n：

年卷期：

2024 年 6 卷 7 期

页   码：

摘   要：

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes(1). 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(2) 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 beta-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 beta-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and beta-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a beta-arrestin dependency and genetic ablation of beta-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of beta-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.