Role of IRF3 in Energy and Glucose Homeostasis

IRF3 在能量和血糖稳态中的作用

• 批准号: 10264168
• 负责人: Evan D Rosen
• 金额: $ 66.22万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264168
• 关键词: Ablation; Accounting; Address; Adipocytes; Adipose tissue; Adverse effects; Affect; Antisense Oligonucleotides; Area; Body Weight; Brown Fat; Cellular biology; Chronic; Coupled; Data; Environment; Family; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Funding; Gap Junctions; Gene Expression; Genes; Genetic Transcription; Genomics; Glycolysis; Goals; Health; Hepatocyte; IRF3 gene; ISG15 gene; Immune; Immune signaling; Immunity; Impairment; Inflammation; Inflammation Mediators; Inflammatory Response; Institutes; Insulin; Insulin Resistance; Interferons; Knowledge; Kupffer Cells; Laboratories; Lead; Link; Liver; Lysine; Mediating; Mediator of activation protein; Metabolic; Metabolic Control; Metabolic dysfunction; Metabolism; Molecular; Mus; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overnutrition; Pathway interactions; Peripheral; Phenocopy; Phenotype; Physiological; Play; Positioning Attribute; Process; Proteins; Publishing; Reagent; Repression; Research Personnel; Resistance; Resolution; Role; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Thermogenesis; Tissues; Transcriptional Regulation; Transgenes; Tumor-infiltrating immune cells; Ubiquitin; Weight Gain; Work; blood glucose regulation; cell type; cytokine; endophenotype; enzyme activity; epigenomics; experimental study; falls; feeding; human disease; improved; in vivo; insulin sensitivity; insulin signaling; macrophage; member; programs; response; systemic inflammatory response; tool; transcription factor; ubiquitin-protein ligase

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.

抽象的 肥胖和 2 型糖尿病代表慢性炎症状态。虽然我们已经学会了 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，我们还不了解这些物质的转录机制 发生反应。我们实验室发现了干扰素调节因子（IRF）家族 免疫相关转录因子在代谢相关组织中活跃。我们展示了 IRF3 在肥胖期间尤其会被诱导，并介导许多不利影响 营养过剩，包括体重增加、棕色脂肪功能抑制、胰岛素抵抗和 肝脂肪变性。我们继续证明 IRF3 在脂肪细胞和 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。在当前的提案中，我们将 通过关注 IRF3 的作用来增进我们对 IRF3 和代谢功能的了解 巨噬细胞，特别是脂肪组织巨噬细胞和肝脏的库普弗细胞。 此外，我们将确定 ISG15 抑制脂肪褐变的机制 和产热作用。最后，我们将对脂肪、肝脏、 和巨噬细胞，以确定代谢和炎症关系的新途径 可能适合治疗干预。