Article Text
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.
- diabetes mellitus
- type 2
- inflammation
- receptors
- G-protein-coupled
- chemokines
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Supplementary materials
Supplementary Data
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Footnotes
DMR, HLK and AJM contributed equally.
Contributors DMR: Conceptualization, formal analysis, investigation, writing—original draft, supervision, project administration. HLK: Conceptualization, formal analysis, investigation, writing—original draft. AJM: Conceptualization, formal analysis, investigation, writing—original draft. SB-G: Investigation, formal analysis. RDlFG: Investigation, formal analysis. JM: Investigation, formal analysis. MZ: Formal analysis, data curation. SF: Resources. TLP: Investigation. ND: Investigation. PR: Investigation. AE-O: Data Curation. J-FG: Resources. NV: Resources. WNC: Writing—review and editing, funding acquisition. AC: Writing—review and editing, funding acquisition. PMS: Writing—review and editing, funding acquisition. RJS: Writing—review and editing, funding acquisition. MAF: Conceptualization, writing—review and editing. PD: Conceptualization, writing—review and editing, funding acquisition. CJL: Conceptualization, formal analysis, writing—review and editing, supervision, project administration, funding acquisition. DMR and CJL are responsible for the overall content as the guarantor.
Funding The study was funded by Servier.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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