PT  - JOURNAL ARTICLE
AU  - Darren M Riddy
AU  - Helene L Kammoun
AU  - Andrew J Murphy
AU  - Sanja Bosnyak-Gladovic
AU  - Rocio De la Fuente Gonzalez
AU  - Jon Merlin
AU  - Mark Ziemann
AU  - Stewart Fabb
AU  - Tracie L Pierce
AU  - Natalie Diepenhorst
AU  - Patricia Rueda
AU  - Assam El-Osta
AU  - Jean-Francois Gautier
AU  - Nicolas Venteclef
AU  - William N Charman
AU  - Arthur Christopoulos
AU  - Patrick M Sexton
AU  - Roger J Summers
AU  - Mark A Febbraio
AU  - Philippe Delerive
AU  - Christopher J Langmead
TI  - Deletion of GPR21 improves glucose homeostasis and inhibits the CCL2-CCR2 axis by divergent mechanisms
AID  - 10.1136/bmjdrc-2021-002285
DP  - 2021 Nov 01
TA  - BMJ Open Diabetes Research & Care
PG  - e002285
VI  - 9
IP  - 2
4099  - http://drc.bmj.com/content/9/2/e002285.short
4100  - http://drc.bmj.com/content/9/2/e002285.full
SO  - BMJ Open Diab Res Care2021 Nov 01; 9
AB  - 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.All data relevant to the study are included in the article or uploaded as supplementary information.