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

Darren M. Riddy, Helene L. Kammoun, Andrew J. Murphy, Sanja Bosnyak-Gladovic, Rocio De La Fuente Gonzalez, Jon Merlin, Mark Ziemann, Stewart Fabb, Tracie L. Pierce, Natalie Diepenhorst, Patricia Rueda, Assam El-Osta, Jean Francois Gautier, Nicolas Venteclef, William N. Charman, Arthur Christopoulos, Patrick M. Sexton, Roger J. Summers, Mark A. Febbraio, Philippe DeleriveChristopher J. Langmead

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4 Citations (Scopus)


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.

Original languageEnglish
Article numbere002285
Number of pages13
JournalBMJ Open Diabetes Research and Care
Issue number2
Publication statusPublished - Nov 2021


  • chemokines
  • diabetes mellitus
  • G-protein-coupled
  • inflammation
  • receptors
  • type 2

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