Role of IRF3 in Energy and Glucose Homeostasis

摘要 肥胖和2型糖尿病代表慢性炎症状态。在我们了解到 关于免疫的可溶性介质和信号中间体如何破坏正常的许多问题 代谢功能，我们还不知道这些基因的转录机制 响应就会发生。我们实验室发现，干扰素调节因子(IRFs)家族 在免疫相关的转录因子中，都活跃在与代谢相关的组织中。我们展示了 特别是IRF3在肥胖期间被诱导，并介导了许多不良反应 营养过剩，包括体重增加，棕色脂肪功能抑制，胰岛素抵抗，以及 肝脏脂肪变性。我们进一步证明了IRF3在脂肪细胞中发挥着不同的功能 肝细胞，对代谢参数有不同的影响。我们还确定了一个关键的下游 IRF3靶标ISG15，作为IRF3在FAT中作用的介体。在目前的提案中，我们将 通过重点研究IRF3在体内的作用，加深我们对IRF3及其代谢功能的认识 巨噬细胞，尤其是脂肪组织中的巨噬细胞和肝脏的枯否细胞。 此外，我们将确定ISG15抑制脂肪褐变的机制 和生热作用。最后，我们将对脂肪、肝脏、 和巨噬细胞，以确定新陈代谢和炎症连接点的新途径 可能要接受治疗干预。

ABSTRACT Obesity and Type 2 diabetes represent states of chronic inflammation. While we have learned much about how the soluble mediators and signaling intermediates of immunity disrupt normal metabolic function, we do not yet understand the transcriptional mechanisms by which these responses occur. Our laboratory has discovered that interferon regulatory factors (IRFs), a family of immune-related transcription factors, are active in tissues of metabolic relevance. We showed that IRF3 in particular becomes induced during obesity, and mediates many of the adverse effects of overnutrition, including weight gain, suppression of brown fat function, insulin resistance, and hepatic steatosis. We have gone on to show that IRF3 exerts distinct functions in adipocytes and hepatocytes, with differential effects on metabolic parameters. We also identify a key downstream IRF3 target, ISG15, as a mediator of the actions of IRF3 in fat. In the current proposal, we will advance our knowledge of IRF3 and metabolic function by focusing on its actions in macrophages, specifically in adipose tissue macrophages and Kupffer cells of the liver. Furthermore, we will determine the mechanisms by which ISG15 represses adipose browning and thermogenesis. Finally, we will pursue an unbiased analysis of IRF3 target genes in fat, liver, and macrophages, to determine new pathways at the nexus of metabolism and inflammation that may be amenable to therapeutic intervention.