Deletion of GPR21 improves glucose homeostasis and inhibits the CCL2-CCR2 axis by divergent mechanisms.

Autor:	Riddy DM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia darren.riddy@monash.edu chris.langmead@monash.edu., Kammoun HL; Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia., Murphy AJ; Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia., Bosnyak-Gladovic S; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., De la Fuente Gonzalez R; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Merlin J; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Ziemann M; Department of Diabetes, Monash University Central Clinical School, Melbourne, Victoria, Australia., Fabb S; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Pierce TL; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Diepenhorst N; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Rueda P; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., El-Osta A; Department of Diabetes, Monash University Central Clinical School, Melbourne, Victoria, Australia., Gautier JF; Inserm UMRS 1138, Département Diabète et Endocrinologie, Sorbonne Université, Paris, France., Venteclef N; Inserm UMRS 1138, Département Diabète et Endocrinologie, Sorbonne Université, Paris, France., Charman WN; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Christopoulos A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Sexton PM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Summers RJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Febbraio MA; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Delerive P; Pôle d'Innovation Thérapeutique Métabolisme, Institut de Recherches Internationales Servier, Suresnes, France., Langmead CJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia darren.riddy@monash.edu chris.langmead@monash.edu.
Jazyk:	angličtina
Zdroj:	BMJ open diabetes research & care [BMJ Open Diabetes Res Care] 2021 Nov; Vol. 9 (2).
DOI:	10.1136/bmjdrc-2021-002285
Abstrakt:	Introduction: A potential role for the orphan G protein-coupled receptor, GPR21, in linking immune cell infiltration into tissues and obesity-induced insulin resistance has been proposed, although limited studies in mice are complicated by non-selective deletion of Gpr21 . Research Design and Methods: We hypothesized that a Gpr21 -selective knockout mouse model, coupled with type 2 diabetes patient samples, would clarify these issues and enable clear assessment of GPR21 as a potential therapeutic target. Results: High-fat feeding studies in Gpr21 -/- mice revealed improved glucose tolerance and modest changes in inflammatory gene expression. Gpr21 -/- monocytes and intraperitoneal macrophages had selectively impaired chemotactic responses to monocyte chemoattractant protein (MCP)-1, despite unaltered expression of Ccr2 . Further genotypic analysis revealed that chemotactic impairment was due to dysregulated monocyte polarization. Patient samples revealed elevated GPR21 expression in peripheral blood mononuclear cells in type 2 diabetes, which was correlated with both %HbA1c and fasting plasma glucose levels. Conclusions: Collectively, human and mouse data suggest that GPR21 influences both glucose homeostasis and MCP-1/CCL2-CCR2-driven monocyte migration. However, a Gpr21 -/- bone marrow transplantation and high-fat feeding study in mice revealed no effect on glucose homeostasis, suggesting that there is no (or limited) overlap in the mechanism involved for monocyte-driven inflammation and glucose homeostasis. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu