Article Text

Deletion of GPR21 improves glucose homeostasis and inhibits the CCL2-CCR2 axis by divergent mechanisms
  1. Darren M Riddy1,
  2. Helene L Kammoun2,
  3. Andrew J Murphy2,
  4. Sanja Bosnyak-Gladovic1,
  5. Rocio De la Fuente Gonzalez1,
  6. Jon Merlin1,
  7. Mark Ziemann3,
  8. Stewart Fabb1,
  9. Tracie L Pierce1,
  10. Natalie Diepenhorst1,
  11. Patricia Rueda1,
  12. Assam El-Osta3,
  13. Jean-Francois Gautier4,
  14. Nicolas Venteclef4,
  15. William N Charman1,
  16. Arthur Christopoulos1,
  17. Patrick M Sexton1,
  18. Roger J Summers1,
  19. Mark A Febbraio1,
  20. Philippe Delerive5,
  21. Christopher J Langmead1
  1. 1Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
  2. 2Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
  3. 3Department of Diabetes, Monash University Central Clinical School, Melbourne, Victoria, Australia
  4. 4Inserm UMRS 1138, Département Diabète et Endocrinologie, Sorbonne Université, Paris, France
  5. 5Pôle d'Innovation Thérapeutique Métabolisme, Institut de Recherches Internationales Servier, Suresnes, France
  1. Correspondence to Dr Darren M Riddy; darren.riddy{at}monash.edu; Professor Christopher J Langmead; chris.langmead{at}monash.edu

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.

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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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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