Role of IRF3 in Energy and Glucose Homeostasis

摘要 肥胖和2型糖尿病代表慢性炎症的状态。虽然我们知道 关于免疫的可溶性介质和信号中间体如何破坏正常的 代谢功能，我们还不了解这些转录机制， 反应发生。我们的实验室发现干扰素调节因子（IRFs）是一个家族， 免疫相关的转录因子，在代谢相关的组织中活跃。我们展示 IRF3在肥胖期间特别被诱导，并介导许多不良反应， 营养过剩，包括体重增加，抑制棕色脂肪功能，胰岛素抵抗， 肝脂肪变性我们已经继续表明IRF3在脂肪细胞中发挥不同的功能， 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在脂肪中作用的介体。在目前的提案中，我们将 通过关注IRF3在以下方面的作用，推进我们对IRF3和代谢功能的认识： 巨噬细胞，特别是脂肪组织巨噬细胞和肝脏的枯否细胞。 此外，我们将确定ISG 15抑制脂肪布朗宁的机制 和产热作用。最后，我们将对脂肪，肝脏， 和巨噬细胞，以确定代谢和炎症的新途径， 可以进行治疗干预。

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.