Role of IRF3 in Energy and Glucose Homeostasis

IRF3 在能量和血糖稳态中的作用

• 批准号: 9043054
• 负责人: Evan D Rosen
• 金额: $ 39.15万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043054
• 关键词: Adipocytes; Adipose tissue; Affect; Animals; Area; Attention; Binding; Burn injury; Catecholamines; Cell Nucleus; Cells; Cellular biology; Chronic; Coupled; Cytosol; Data; Environment; Exposure to; FDA approved; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Targeting; Genetic; Genetic Epistasis; Glucose Intolerance; Goals; Health; High Fat Diet; IRF3 gene; IRF4 gene; Immune; Immunity; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Institutes; Insulin; Interferons; Knockout Mice; Knowledge; Laboratories; Lead; Learning; Link; Lipids; Lipolysis; Liver; Maps; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overnutrition; Pathway interactions; Peripheral; Phenocopy; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Positioning Attribute; Process; Proteins; Reagent; Role; Signal Pathway; Signal Transduction; TBK1 gene; TLR4 gene; Techniques; Testing; Thermogenesis; Thinking; Thinness; Tissues; Transcription Coactivator; Transgenes; Work; adipocyte differentiation; amlexanox; arm; blood glucose regulation; cell type; cytokine; design; epigenomics; fatty acid oxidation; feeding; human disease; improved; in vivo; inhibitor/antagonist; insulin sensitivity; insulin signaling; interest; lipid biosynthesis; loss of function; mRNA Expression; research study; transcription factor

 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.

 描述（由申请人提供）：肥胖和2型糖尿病代表慢性炎症状态，并且对于免疫的可溶性介质和信号中间体如何破坏正常代谢功能已经了解很多。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。我们实验室发现干扰素调节因子（IRF）在脂肪组织中表达，其中IRF4在脂肪细胞分化、脂肪分解和脂肪生成中发挥着重要作用。在当前的提案中，我们重点关注相关分子 IRF3，它是一种经过充分研究的促炎转录因子。 IRF3 具有特殊性 之所以引起人们的兴趣，是因为它被两种激酶 TBK1 和 IKKe 激活，已知这两种激酶在肥胖中会上调。此外，IKKe 的药理学或遗传破坏可促进高脂肪喂养小鼠的瘦身和胰岛素敏感性。有趣的是，我们发现缺乏 IRF3 的小鼠似乎表现出这些效应，并显示出肥胖减少，白色脂肪产热增强（即“褐变”）。此外，Irf3-/- 小鼠完全免受肝脂肪变性的影响。我们现在已经证明IRF3结合并抑制转录共激活剂PGC-1a，并且我们假设Irf3-/-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，我们描述了确定 IRF3 是否在肥胖动物的肝脏和脂肪中被激活的实验，并研究 IRF3 抑制产热和脂肪酸氧化的机制。