Inflammation, Insulin Resistance, and Foxo factors

描述（由申请人提供）：肥胖症的流行导致胰岛素抵抗，最终导致II型糖尿病，这已被世界卫生组织充分记录。这种疾病的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成分才刚刚开始被解开。特别是，适应性免疫系统，特别是T细胞似乎发挥了重要作用。在肥胖状态下，CD4和CD8 T细胞都浸润脂肪组织，并且它们被认为具有相反的作用。CD8 T细胞是促炎性的，并加速炎性巨噬细胞的发展，而Th2细胞和T调节细胞形式的CD4 T细胞似乎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细胞亚群的转基因小鼠的胰岛素抵抗进展。其中包括一种小鼠 缺乏制造抗炎Th2细胞的能力。其次，我们发现脂肪组织中的T调节细胞表达一种独特的趋化因子受体，我们认为这种受体使它们定位于白色脂肪。我们建议生产和测试在调节细胞中缺乏这种趋化因子受体的小鼠，并用这些小鼠确定缺乏脂肪定位的T调节细胞是否会影响高脂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和免疫系统的炎症状态升高之间存在联系。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转录因子的小鼠如何在高脂肪饮食的条件下进展为胰岛素抵抗。这些实验将大大提高我们对生物体代谢和免疫系统之间界面的认识。

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.