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并最终导致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刚刚开始被解开。特别是适应性免疫系统，尤其是T细胞似乎起着重要的作用。在肥胖状态下，CD4和CD8 T细胞浸润脂肪组织，它们被认为具有相反的作用。CD8 T细胞具有促炎作用，加速炎性巨噬细胞的发展，而CD4 T细胞以Th2细胞和T调节细胞的形式出现，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建议。首先，我们将测试缺乏不同T细胞亚群的转基因小鼠，以研究胰岛素抵抗的进展。这包括一种老鼠

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.