Inflammation, Insulin Resistance, and Foxo factors

描述（由申请人提供）：世界卫生组织已经详细记录了肥胖的流行导致胰岛素抵抗并最终导致 II 型糖尿病。这种疾病过程起源于免疫炎症，而驱动胰岛素抵抗的免疫系统的特定组成部分才刚刚开始被揭开。特别是，适应性免疫系统，尤其是 T 细胞似乎发挥着重要作用。 CD4 和 CD8 T 细胞在肥胖状态下都会浸润脂肪组织，并且它们被认为具有相反的作用。 CD8 T 细胞具有促炎性，可加速炎症巨噬细胞的发育，而 Th2 细胞和 T 调节细胞形式的 CD4 T 细胞似乎可以抑制巨噬细胞介导的炎症。这是一项利用小鼠遗传学以新颖的方式解决这些问题的提议。首先，我们将测试缺乏不同 T 细胞亚群的基因改造小鼠是否会发展为胰岛素抵抗。这包括小鼠品系 缺乏产生抗炎 Th2 细胞的能力。其次，我们发现脂肪组织中的 T 调节细胞独特地表达趋化因子受体，我们认为这种受体可以使它们定位于白色脂肪。我们建议生产并测试调节细胞中特别缺乏这种趋化因子受体的小鼠，并用这些小鼠确定脂肪局部 T 调节细胞的缺乏是否会影响高脂肪饮食诱导的与糖尿病进展相关的代谢变化。最后，我们提出了一个新的假设，即 Foxo 转录因子在肥胖引起的内分泌变化与免疫系统炎症状态加剧之间存在联系。描述了分析 Foxo 转录因子在各种代谢状态下的活性的实验，以及缺乏 Foxo 转录因子的小鼠在高脂肪饮食条件下如何进展为胰岛素抵抗。这些实验将极大地增强我们对有机体代谢和免疫系统之间相互作用的了解。

DESCRIPTION (provided by applicant): The epidemic of obesity leading to insulin resistance and eventually Type II diabetes has been well documented by the World Health Organization. This disease process originates with immune inflammation, and the specific components of the immune system that drive insulin resistance are just beginning to be unraveled. In particular, the adaptive immune system and especially T cells appear to play an important role. Both CD4 and CD8 T cell infiltrate adipose tissue in the obese state, and they are proposed to have opposing effects. CD8 T cells are proinflammatory, and accelerate the development of inflammatory macrophages, whereas CD4 T cells in the form of Th2 cells and T regulatory cells appear to suppress macrophage-mediated inflammation. This is a proposal to use mouse genetics to address these questions in novel ways. First, we will test genetically altered mice that lack difference T cell subsets for the progression to insulin resistance. This includes a strain of mice that lacks the ability to make anti-inflammatory Th2 cells. Second, we have discovered that T regulatory cells in the adipose tissue uniquely express a chemokine receptor that we propose allows them to localize to white fat. We propose to produce and test mice that lack this chemokine receptor specifically in regulatory cells, and with these mice determine whether a lack fat-localized T regulatory cells affect the high fat diet induced metabolic changes associated with progression to diabetes. Finally, we propose the novel hypothesis that Foxo transcription factors present a connection between the endocrine changes that occur as a result of obesity and the heightened inflammatory state of the immune system. Experiments are described that analyze the activity of Foxo transcription factors in various metabolic states, and furthermore how mice lacking Foxo transcription factors progress to insulin resistance under conditions of a high fat diet. These experiments will greatly enhance our knowledge of the interface between organismal metabolism and the immune system.