GPR105 ablation prevents inflammation and improves insulin sensitivity in mice with diet-induced obesity

Jianfeng Xu, Hidetaka Morinaga, Dayoung Oh, Pingping Li, Ai Chen, Saswata Talukdar, Eduardo Lazarowski, Jerrold M. Olefsky, Jane J. Kim

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

GPR105, a G protein-coupled receptor for UDP-glucose, is highly expressed in several human tissues and participates in the innate immune response. Because inflammation has been implicated as a key initial trigger for type 2 diabetes, we hypothesized that GPR105 (official gene name: P2RY14) might play a role in the initiation of inflammation and insulin resistance in obesity. To this end, we investigated glucose metabolism in GPR105 knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD). We also examined whether GPR105 regulates macrophage recruitment to liver or adipose tissues by in vivo monocyte tracking and in vitro chemotaxis experiments, followed by transplantation of bone marrow from either KO or WT donors to WT recipients. Our data show that genetic deletion of GPR105 confers protection against HFD-induced insulin resistance, with reduced macrophage infiltration and inflammation in liver, and increased insulin-stimulated Akt phosphorylation in liver, muscle, and adipose tissue. By tracking monocytes from either KO or WT donors, we found that fewer KO monocytes were recruited to the liver of WT recipients. Furthermore, we observed that uridine 5-diphosphoglucose enhanced the in vitro migration of bone marrow-derived macrophages from WT but not KO mice, and that plasma uridine 5-diphosphoglucose levels were significantly higher in obese versus lean mice. Finally, we confirmed that insulin sensitivity improved in HFD mice with a myeloid cell-specific deletion of GPR105. These studies indicate that GPR105 ablation mitigates HFD-induced insulin resistance by inhibiting macrophage recruitment and tissue inflammation. Hence GPR105 provides a novel link between innate immunity and metabolism.

Original languageEnglish (US)
Pages (from-to)1992-1999
Number of pages8
JournalJournal of Immunology
Volume189
Issue number4
DOIs
StatePublished - Aug 15 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Xu, J., Morinaga, H., Oh, D., Li, P., Chen, A., Talukdar, S., Lazarowski, E., Olefsky, J. M., & Kim, J. J. (2012). GPR105 ablation prevents inflammation and improves insulin sensitivity in mice with diet-induced obesity. Journal of Immunology, 189(4), 1992-1999. https://doi.org/10.4049/jimmunol.1103207