Inflammation, Insulin Resistance, and Foxo factors

描述(申请人提供)：肥胖的流行导致胰岛素抵抗，最终导致II型糖尿病，世界卫生组织已经很好地记录了这一现象。这一疾病过程始于免疫炎症，而驱动胰岛素抵抗的免疫系统特定组件才刚刚开始解体。特别是，适应性免疫系统，特别是T细胞似乎扮演着重要的角色。在肥胖状态下，CD4和CD8T细胞都会渗透到脂肪组织中，它们被认为具有相反的作用。CD8T细胞是促炎细胞，促进炎症巨噬细胞的发展，而以Th2细胞和T调节细胞形式存在的CD4T细胞似乎抑制巨噬细胞介导的炎症。这是一项利用老鼠遗传学以新颖的方式解决这些问题的提议。首先，我们将测试缺乏差异T细胞亚群的转基因小鼠的胰岛素抵抗进展情况。这包括一种品系的小鼠 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调节细胞独特地表达一种趋化因子受体，我们提出的这种受体可以使它们定位于白色脂肪。我们建议培育和测试在调节细胞中缺乏这种趋化因子受体的小鼠，并用这些小鼠来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高度炎症状态之间存在联系。描述了分析FOXO转录因子在不同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生物新陈代谢和免疫系统之间的接口的了解。

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.