Role of IRF3 in Energy and Glucose Homeostasis

 描述（由申请人提供）：肥胖和2型糖尿病代表慢性炎症的状态，并且已经了解了免疫的可溶性介质和信号传导中间体如何破坏正常代谢功能。然而，我们还不了解免疫因子与代谢机制相互作用的转录机制。我们的实验室已经发现干扰素调节因子（IRFs）在脂肪组织中表达，并且IRF 4特别在脂肪细胞分化、脂解和脂肪生成中起主要作用。在目前的建议中，我们专注于相关分子IRF 3，这是一个研究充分的促炎转录因子。IRF 3特别是 因为它被两种激酶TBK 1和IKKe激活，已知这两种激酶在肥胖症中上调。此外，IKKe的药理学或遗传破坏促进高脂肪喂养小鼠的瘦和胰岛素敏感性。有趣的是，我们已经发现缺乏IRF 3的小鼠似乎表现出这些效应，并且显示出减少的肥胖和增强的白色脂肪产热（即“褐变”）。此外，Irf 3-/-小鼠完全免于肝脂肪变性。我们现在已经表明，IRF 3结合并抑制转录共激活因子PGC-1a，我们假设Irf 3-/-小鼠的表型可能反映了未经检查的PGC-1a活性的获得。在这里，我们描述的实验，以确定是否IRF 3被激活的肝脏和脂肪的肥胖动物，并研究IRF 3的作用，以抑制产热和脂肪酸氧化的机制。

 DESCRIPTION (provided by applicant): Obesity and Type 2 diabetes represent states of chronic inflammation, and much has been learned about how the soluble mediators and signaling intermediates of immunity disrupt normal metabolic function. We do not yet understand, however, the transcriptional mechanisms by which immune factors interact with the metabolic machinery. Our laboratory has discovered that interferon regulatory factors (IRFs) are expressed in adipose tissue and that IRF4 in particular plays a major role in adipocyte differentiation, lipolysis and lipogenesis. In the current proposal, we focus on the related molecule IRF3, which is a well-studied pro-inflammatory transcription factor. IRF3 is of particular interest because it is activated by two kinases, TBK1 and IKKe, that are known to be up-regulated in obesity. Furthermore, pharmacological or genetic disruption of IKKe promotes leanness and insulin sensitivity in high-fat fed mice. Interestingly, we have discovered that mice lacking IRF3 appear to phenocopy these effects, and show reduced adiposity with enhanced thermogenesis in white fat (i.e. `browning'). Furthermore, Irf3-/- mice are completely protected from hepatic steatosis. We have now shown that IRF3 binds to and inhibits the transcriptional co-activator PGC-1a, and we hypothesize that the phenotype of the Irf3-/- mice may reflect the acquisition of unchecked PGC-1a activity. Here we describe experiments to determine if IRF3 is activated in liver and fat of obese animals, and to study the mechanisms by which IRF3 acts to inhibit thermogenesis and fatty acid oxidation.