Deletion of GPR21 improves glucose homeostasis and inhibits the CCL2-CCR2 axis by divergent mechanisms. Issue 2 (15th November 2021)

• Record Type: Journal Article
• Authors: Riddy, Darren M; Kammoun, Helene L; Murphy, Andrew J; Bosnyak-Gladovic, Sanja; De la Fuente Gonzalez, Rocio; Merlin, Jon; Ziemann, Mark; Fabb, Stewart; Pierce, Tracie L; Diepenhorst, Natalie; Rueda, Patricia; El-Osta, Assam; Gautier, Jean-Francois; Venteclef, Nicolas; Charman, William N; Christopoulos, Arthur; Sexton, Patrick M; Summers, Roger J; Febbraio, Mark A; Delerive, Philippe; Langmead, Christopher J
• Is Part Of: BMJ open diabetes research and care. Volume 9:Issue 2(2021)
• Publication Date: 2021-11-15
• Subjects: diabetes mellitus -- type 2 -- inflammation -- receptors -- G-protein-coupled -- chemokines; Diabetes -- Periodicals; 616.462005
• DOI: 10.1136/bmjdrc-2021-002285
• Languages: English
• ISSNs: 2052-4897

Abstract

Abstract : 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.