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.

Instmctions）： 慢性组织炎症是降低与胰岛素敏感性降低的重要原因 肥胖/2型糖尿病，巨噬细胞脂肪细胞轴是引起这种代谢的关键效应器 缺点。我们最近对这个问题采取了一种新方法，并产生了特定于脂肪细胞的方法 NCOR KO小鼠（Ako小鼠）。在Ako动物中，PPary成为组成性活跃，导致强大的抗抗活性 炎症性胰岛素敏感表型。我们还发现丝氨酸273处的PPARY磷酸化为 当Ncor在脂肪细胞中删除时显着钝化。在此应用程序中，我们提出了几个新的 假设可以解释Ako小鼠中胰岛素敏感性的假设，这些胰岛素敏感性导致了许多研究 检查丝氨酸273丝氨酸磷酸化的调节和此的功能性预言 受体的非磷酸化形式。我们还将进行一系列分子研究以识别 来自WT和Ako小鼠的原发性脂肪细胞的全局基因表达模式以及全局DNA PPARY，NCOR和SMRT的结合位点（CISTROMES）。我们还假设中央生理学 导致AKO小鼠胰岛素耐药性的机制是NCOR的缺失导致细胞 PPARY的自主激活。因此，导致趋化信号传导降低，脂肪降低 组织巨噬细胞含量，炎症降低和胰岛素敏感性提高。在这种情况下，我们 已经提出了新的观察结果，表明白细胞趋化因子LBT4及其受体BLT1可能 在巨噬细胞迁移到脂肪组织中起主要作用。因此，我们有吸引人的新数据 表明用BLT1抑制剂处理巨噬细胞可显着降低巨噬细胞趋化性 体外和用BLT1抑制剂治疗肥胖小鼠会导致葡萄糖的良好改善 耐受性和胰岛素敏感性。提出了一种在体外和体内方法的组合方法来检验假设 从这些新数据中生成。这些后者的研究具有很强的翻译意义，因为BLT1可以 成为胰岛素敏化药物发现的重要新靶标。 相关性（请参阅Instmctions）： 拟议的研究将直接有助于我们对调节起始机制的理解， 炎症的致病形式的扩增和解决，促进胰岛素抵抗和 2型糖尿病的发展。