Role of IRF3 in Energy and Glucose Homeostasis

 描述(申请人提供)：肥胖和2型糖尿病代表慢性炎症状态，关于免疫的可溶性介质和信号中间体如何扰乱正常代谢功能已有许多研究。然而，我们还不了解免疫因子与新陈代谢机制相互作用的转录机制。我们的实验室发现，干扰素调节因子(IRFs)在脂肪组织中表达，尤其是IRF4在脂肪细胞分化、脂肪分解和脂肪生成中发挥重要作用。在目前的提案中，我们将重点放在相关分子IRF3上，它是一个研究得很好的促炎转录因子。IRF3具有特殊的特性 这是因为它是由两种已知在肥胖中上调的激酶--TBK1和IKKE激活的。此外，IKKE的药理或遗传干扰可促进高脂饮食小鼠的瘦身和胰岛素敏感性。有趣的是，我们已经发现，缺乏IRF3的小鼠似乎表现出这些效应，并通过增强白色脂肪的产热作用(即“褐变”)显示出减少的肥胖度。此外，IRF3-/-小鼠完全免受肝脏脂肪变性的影响。我们现在已经证明IRF3结合并抑制转录共激活因子PGC-1a，我们假设IRF3-/-小鼠的表型可能反映了未受抑制的PGC-1a活性的获得。在这里，我们描述了实验，以确定IRF3是否在肥胖动物的肝脏和脂肪中被激活，并研究IRF3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.