Function of PPAR gamma-dependent gene networks in macrophages

过氧化物酶体增殖物激活受体γ（PPAR γ）调节脂肪细胞分化和葡萄糖 是噻唑烷二酮类药物的分子靶点，噻唑烷二酮类药物可作为胰岛素增敏剂， 2型糖尿病PPAR？也在巨噬细胞中表达，并负调节 通过抑制AP-1和NK-κ B依赖性基因的子集来抑制巨噬细胞活化。最近发现 巨噬细胞积聚在肥胖脂肪组织中，是炎症介质的主要来源， 与胰岛素抵抗有关，这增加了巨噬细胞是抗糖尿病药物的关键靶点的可能性。 TZD的作用。与此一致，选择性删除的过氧化物酶体增殖物激活受体？来自巨噬细胞的基因导致轻度 瘦动物的胰岛素抵抗和饮食诱导的肥胖症中更严重程度的胰岛素抵抗。 与罗森菲尔德实验室合作进行的研究发现了一种机制途径， 什么是PPARs？抑制激活的巨噬细胞中涉及核的炎症基因表达 受体辅阻遏物。本项目将测试脂肪细胞-巨噬细胞 相互作用驱动导致胰岛素抵抗的基因表达的炎症程序， TZD作为胰岛素增敏剂部分通过反调节巨噬细胞中的这些反应。四个具体 提出的目标：具体目标i将定义PPAR？巨噬细胞中N-CoR依赖的基因网络 使用基因表达谱和ChIP芯片技术的组合。这些研究将测试 假设N-CoR辅阻遏物复合物是PPAR所必需的？介导的抑制广泛的 炎症反应基因和将补充项目2中的研究， 用N-CoR缺陷型巨噬细胞重建的小鼠。具体目标2将研究胰岛素抵抗的基础 选择性缺乏过氧化物酶体增殖物激活受体的小鼠在巨噬细胞中表达。与Project i合作， 这些研究将评估巨噬细胞在脂肪组织、骨骼肌 野生型小鼠和缺乏过氧化物酶体增殖物激活受体的小鼠的肝脏呢？在巨噬细胞中表达。第3章测试 假设PPAR？反调节促炎基因表达程序诱导的自由 脂肪酸这将通过测定游离脂肪酸对巨噬细胞基因的影响来实现。 对照组和PPAR？缺乏的巨噬细胞，并通过评估游离脂肪酸的能力， 刺激PPAR？的反式阻遏活性。具体目标4将利用选择性调节剂的过氧化物酶体增殖物激活受体？到 检验胰岛素增敏活性的过氧化物酶体增殖物激活受体？可以通过激活 直接靶向脂肪细胞中的基因或通过反式阻遏巨噬细胞中的炎症反应基因。 这些研究对治疗肥胖引起的糖尿病的新方法具有意义。

The peroxisome proliferator-activated receptor y (PPAR) regulates adipocyte differentiation and glucose homeostasis and is the molecular target of thiazolidinediones that act as insulin-sensitizers in patients with type 2 diabetes. PPAR? is also expressed in macrophages and negatively regulates the program of macrophage activation by repressing a subset of AP-i and NK-KB-dependent genes. The recent discovery that macrophages accumulate in obese adipose tissue and are a major source of inflammatory mediators that are linked to insulin resistance raises the possibility that the macrophage is a key target of the anti-diabetic actions of TZDs. Consistent with this, selective deletion of the PPAR? gene from macrophages results in mild insulin resistance in lean animals and a more severe degree of insulin resistance in diet-induced obesity. Studies performed in collaboration with the Rosenfeld laboratory have uncovered a mechanistic pathway by which PPAR? inhibits inflammatory gene expression in activated macrophages that involves the nuclear receptor co-repressor, N-CoR. This Project will test the overall hypothesis that adipocyte-macrophage interactions drive inflammatory programs of gene expression that contribute to insulin resistance and that TZDs act as insulin sensitizers in part by counter-regulating these responses in macrophages. Four Specific Aims are proposed: Specific Aim i will define PPAR? and N-CoR-dependent gene networks in macrophages using a combination of gene expression profiling and ChlP-Chip technologies. These studies will test the hypothesis that N-CoR co-repressor complexes are required for PPAR?-mediated repression of broad sets of inflammatory response genes and will complement studies in Project 2 examining glucose homeostasis in mice reconstituted with N-CoR-deficient macrophages. Specific Aim 2 will investigate the basis for insulinresistance in mice selectively lacking PPAR? expression in macrophages. In collaboration with Project i, these studies will evaluate macrophage accumulation and gene expression in adipose tissue, skeletal muscle and livers of wild type mice and mice lacking PPAR? expression in macrophages. Specific Aim 3 will test the hypothesis that PPAR? counter-regulates pro-inflammatory programs of gene expression induced by free fatty acids. This will be accomplished by determining the effects of free fatty acids on macrophage gene expression in control and PPAR?-deficient macrophages and by evaluating the ability of free fatty acids to stimulate the transrepression activities of PPAR?. Specific Aim 4 will utilize selective modulators of PPAR? to test the hypothesis that insulin-sensitizing activities of PPAR? can be achieved through either activation of direct target genes in adipocytes or through transrepression of inflammatory response genes in macrophages. These studies have implications for novel approaches to treatment of obesity-induced diabetes.