In the pathogenesis of insulin
In the pathogenesis of insulin resistance, chronic activation of inflammatory pathways plays an important role, and the macrophage/adipocyte inter-communication provides a key mechanism underlying the common disease states of decreased insulin sensitivity . This involves the migration of macrophages into the adipose tissue with subsequent switching-on of proinflammatory pathways in the macrophages and secretion of cytokines from them. These successive events promote inflammation and decreased insulin sensitivity in nearby cells targeted by insulin , . Because over-nutrition causes a shift in adipocytes to express pro-inflammatory genes, quite a few of which are common to M1 macrophages , we hypothesized that the GPR84 in adipocytes is involved in the inflammatory changes occurring to adipocytes after reaching the status of “diabesity”. In this paper, we present the data showing GPR84 takes part in initiating the insulin resistance in adipocytes under inflammatory circumstances.
Materials and methods
Results and discussion
Introduction Free fatty acids (FFAs) are not only essential nutrients but they also contribute to many cellular functions. FFAs have been demonstrated to act as ligands of several G-protein-coupled receptors (GPCRs) such as Gpr40, Gpr41, Gpr43 and Gpr120 (Ichimura et al., 2009, Briscoe et al., 2003, Itoh et al., 2003, Kotarsky et al., 2003). Gpr41 and Gpr43 can be specifically activated by short-chain FFAs (Brown et al., 2003, Zhang et al., 2013, Covington et al., 2006). Gpr40 is activated by medium- and long-chain FFAs (Mancini and Poitout, 2013, Godinot et al., 2013) and Gpr120 is activated by long-chain FFAs. These fatty Methicillin sodium salt synthesis receptors are suggested to take part in the regulation of energy homeostasis (Briscoe et al., 2003, Itoh et al., 2003, Blad et al., 2012, Oh et al., 2010, Overton et al., 2006, Hirasawa et al., 2005). In the last decade, another receptor Gpr84 was identified to be activated by medium-chain FFAs (MCFAs) with carbon chain lengths of 9–14 (Suzuki et al., 2013). Gpr84 is mainly expressed in immune-related tissues such as bone marrow, spleen, lymph nodes and thymus of mice (Ichimura et al., 2009), and is significantly up-regulated upon lipopolysaccharide (LPS) stimulation (Wang et al., 2006). A study using Gpr84-deficient mice further revealed that Gpr84 can regulate early IL-4 gene expression in activated T cells (Venkataraman and Kuo, 2005). Thus, it is proposed that Gpr84 effects predominately the immune system. Very recently, it was shown that Gpr84 mRNA expression is up-regulated in adipose tissues from C57BL/6J male mice fed with a high-fat diet (Nagasaki et al., 2012). Moreover, MCFAs or surrogate agonists can regulate inflammatory responses through activation of Gpr84 (Wang et al., 2006, Lattin et al., 2008, Suzuki et al., 2013). Compared with the research in mammalian species, little information about Gpr84 is available in fish. In this paper, we explored whether zebrafish Gpr84 (zGpr84) is structurally and functionally similar to that of mammalian species. It was revealed that zGpr84 is involved in the accumulation of lipid droplets and that the up-regulation of zGpr84 can be significantly induced through fasting or treatment of LPS. Furthermore, UA can amplify LPS induced production of the proinflammatory cytokine IL-12 p40 through zGpr84, indicating a possible role of zGpr84 in directly linking fatty acid metabolism to immunological regulation.
Materials and methods
Discussions GPR84 is recently found to be a putative receptor for medium-chain fatty acids (MCFAs). To date, there are only a few published reports with respect to the function of this receptor and little information is available in fish. In this study, we reported the identification and characterization of zGpr84 as well as the investigation of the function of this receptor. zGpr84 mRNA is most abundantly present in liver, heart and intestine among the tested tissues. In human and mouse, GPR84 is expressed predominantly in immune tissues such as bone marrow, peripheral leukocytes, spleen and lymph node (Wang et al., 2006). In zebrafish, the liver and intestine are also the tissues involved in immune defense. The higher expression of this gene in heart, which is not immune-related, is maybe on account of the contamination by lymphocytes when sampled. It would be interesting to further detect the expression of the gene in lymphoid tissues.