Aipocyte/Macrophage Crosstalk in the Etiology of Insulin Resistance.

胰岛素抵抗病因学中的脂细胞/巨噬细胞串扰。

• 批准号: 8472481
• 负责人: jerrold Michael OLEFSKY
• 金额: $ 40.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8472481
• 关键词: Adipocytes; Adipose tissue; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Binding Sites; Biochemical; Biological Assay; CCL2 gene; CDK5 gene; Cells; ChIP-seq; Chemotaxis; Chronic; DNA Binding; Data; Defect; Development; Employee Strikes; Etiology; Event; Exhibits; G Protein-Coupled Receptor Genes; Gap Junctions; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Genetic Transcription; Genomics; Glucose; In Vitro; Inflammation; Insulin; Insulin Resistance; LTB4R gene; Lead; Leukotriene B4; Leukotrienes; Ligands; Measures; Mediating; Metabolic; Methodology; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obese Mice; Obesity; Pattern; Phenocopy; Phenotype; Phosphorylation; Physiological; Play; Principal Investigator; Protein Dephosphorylation; Regulation; Reporting; Repression; Resistance development; Resolution; Role; Series; Serine; Signal Transduction; Syndrome; System; Techniques; Technology; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Up-Regulation; chemokine; chemokine receptor; drug discovery; glucose tolerance; improved; in vivo; inhibitor/antagonist; insulin sensitivity; insulin sensitizing drugs; lipid biosynthesis; macrophage; migration; monocyte; mouse model; novel; novel strategies; receptor; research study; rosiglitazone; small molecule

instmctions): 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. RELEVANCE (See instmctions): The proposed studies will directly contribute to our understanding of mechanisms that regulate the initiation, amplification and resolution of pathogenic forms of inflammation that contribute insulin resistance and the development of type 2 diabetes.

说明）： 慢性组织炎症是与胰岛素抵抗相关的胰岛素敏感性降低的重要因素。 肥胖/2型糖尿病和巨噬细胞脂肪细胞轴是一个关键的效应器，导致这种代谢 缺损我们最近采取了一种新的方法来解决这个问题，并产生了脂肪细胞特异性 NCoR KO小鼠（AKO小鼠）。在AKO动物中，PPARy变得具有组成性活性，导致产生强有力的抗 炎性胰岛素敏感表型。我们还发现，PPARy在丝氨酸273处的磷酸化是一种特异性磷酸化。 当脂肪细胞中的NCoR缺失时显著钝化。在本申请中，我们提出了几个新的 这些假设解释了我们的AKO小鼠的胰岛素敏感性，这些导致了许多研究， 研究丝氨酸273丝氨酸PPARy磷酸化的调节及其功能特性， 受体的非磷酸化形式。我们还将进行一系列的分子研究， 来自WT和AKO小鼠的原代脂肪细胞中的整体基因表达模式，以及整体DNA PPARy、NCoR和SMRT的结合位点（顺式）。我们还假设，中枢生理 导致AKO小鼠胰岛素抵抗的机制是NCoR的缺失导致细胞凋亡。 PPARy的自主激活。因此，导致趋化性信号传导减少， 组织巨噬细胞含量，减少炎症和改善胰岛素敏感性。在这方面我们 最近的研究表明，白三烯趋化因子LBT 4及其受体BLT 1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， 表明用BLT 1抑制剂处理巨噬细胞显著降低了巨噬细胞的趋化性， 而且，用BLT 1抑制剂治疗肥胖小鼠引起葡萄糖的显著改善 耐受性和胰岛素敏感性。提出了一种体外和体内相结合的方法来检验假设 从这些新数据中产生。这些后者的研究具有很强的翻译意义，因为BLT 1可以 成为胰岛素增敏药物发现的重要新靶点。 相关性（见说明）： 拟议的研究将直接有助于我们理解调节启动的机制， 导致胰岛素抵抗的致病性炎症形式的扩增和消退， 2型糖尿病的治疗