Aipocyte/Macrophage Crosstalk in the Etiology of Insulin Resistance.

慢性组织炎症是与肥胖/2型糖尿病相关的胰岛素敏感性降低的重要因素，而巨噬细胞脂肪细胞轴是导致这种代谢缺陷的关键因素。我们最近采取了一种新的方法来解决这个问题，并培育出了脂肪细胞特异性的NCoR KO小鼠(AKO小鼠)。在AKO动物中，PPARy变得结构性活跃，导致强大的抗炎胰岛素敏感表型。我们还发现，当NCoR在脂肪细胞中被删除时，丝氨酸273处的PPARy的磷酸化明显减弱。在这个应用中，我们提出了几个新的假说来解释我们的AKO小鼠的胰岛素敏感性，这导致了一些研究来检验丝氨酸273丝氨酸PPARy磷酸化的调节和功能特性 非磷酸化形式的受体。我们还将进行一系列分子研究，以确定WT和AKO小鼠原代脂肪细胞中的全球基因表达模式，以及PPARy、NCoR和SMRT的全球DNA结合位点(Cistrome)。我们还假设，导致AKO小鼠胰岛素抵抗的中枢生理机制是NCoR基因缺失导致PPARy的细胞自主激活。因此，导致趋化信号减少，脂肪组织巨噬细胞含量减少，炎症减轻，胰岛素敏感性提高。在这种背景下，我们的新观察表明，白三烯趋化因子LBT4及其受体BLT1可能在巨噬细胞迁移到脂肪组织中起主导作用。因此，我们有令人信服的新数据 结果表明，用BLT1抑制剂治疗巨噬细胞在体外显著降低巨噬细胞的趋化能力，用BLT1抑制剂治疗肥胖小鼠可显著改善糖耐量和胰岛素敏感性。提出了一种体外和体内相结合的方法来检验这些假设。 从这些新数据中产生。这些后一项研究具有很强的翻译意义，因为BLT1可能成为胰岛素增敏药物发现的重要新靶点。

Chronic tissue inflammation is an important contributor to the decreased insulin sensitivity associated with obesity/type 2 diabetes and that the macrophage adipocyte axis is a key effector causing this metabolic defect. We have recentiy taken a new approach to this problem and have generated adipocyte-specific NCoR KO mice (AKO mice). In AKO animals, PPARy becomes constitutively active, leading to a robust anti-inflammatory insulin sensitive phenotype. We also find that phosphorylation of PPARy at serine 273 is markedly blunted when NCoR is deleted in adipocytes. In this application, we propose several new hypotheses to explain the insulin sensitivity in our AKO mice and these lead to a number of studies to examine the regulation of serine 273 serine PPARy phosphorylation and the functional propoerties of this non-phosphorylated form of the receptor. We will also conduct a series of molecular studies to identity the global gene expression patterns in primary adipocytes from WT and AKO mice, as well as the global DNA binding sites (cistromes) of PPARy, NCoR and SMRT. We also hypothesize that the central physiologic mechanism leading to the insulin resistance in the AKO mice is that deletion of NCoR leads to cell autonomous activation of PPARy. Thus, causes reduced chemotactic signaling, with decreased adipose tissue macrophage content, decreased inflammation and improved insulin sensitivity. In this context, we have made new observations indicating that the leukotriene chemokine, LBT4, and its receptor BLT1, may play a dominant role in macrophage migration into adipose tissue. Thus, we have compelling new data showing that treatment of macrophages with a BLT1 inhibitor markedly reduces macrophage chemotaxis in vitro and, that treatment of obese mice with the BLT1 inhibitor causes a robust improvement in glucose tolerance and insulin sensitivity. A combined in vitro and in vivo approach is proposed to test the hypotheses generated from these new data. These latter studies have strong translational implications since BLT1 could emerge as an important new target for insulin sensitizing drug discovery.