GPR105 Ablation Prevents Inflammation and Improves Insulin Sensitivity in Mice with Diet-Induced Obesity

Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2012; 189(4):1992-9. DOI: 10.4049/jimmunol.1103207
Source: PubMed


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.

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    • "Early studies proposed a role for the P2Y 14 -R in chemotaxis of hematopoietic stem cells (Lee et al., 2003), and although Arase and coworkers (2009) were unable to illustrate effects of UDPglucose on chemotaxis of neutrophils, they showed that the P2Y 14 -R played a key role in the innate mucosal immunity response of the female reproductive tract. More recently, we directly showed that the P2Y 14 -R promotes Rho-mediated signaling and chemotaxis in human neutrophils (Sesma et al., 2012), and Xu and coworkers (2012) revealed that highfat diet-induced inflammatory responses of the liver are markedly reduced in P2Y 14 -R(2/2) mice (Xu et al., 2012). UDP-glucose increased migration of macrophages isolated from wild-type mice, but had no effect in P2Y 14 -R knock-out animals. "
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