Mediators and Modifiers of NF-kappaB in Insulin Resistance

胰岛素抵抗中 NF-κB 的调节剂和调节剂

• 批准号: 8004598
• 负责人: STEVEN E SHOELSON
• 金额: $ 4.22万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004598
• 关键词: Adenovirus Vector; Animal Model; Animals; Atherosclerosis; Attenuated; Binding; Cardiovascular Diseases; Cells; Chronic; Cultured Cells; Data; Diet; Down-Regulation; Energy Metabolism; Euglycemic Clamping; Fasting; Fatty acid glycerol esters; Feedback; Gene Expression Profiling; Gene Targeting; Genetic Transcription; Glucose; Glucose Clamp; Grant; Host Defense; Human; I Kappa B-Alpha; I-kappa B Proteins; ICAM1 gene; IL6 gene; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interleukin-6; Intervention; Knock-out; Leptin; Link; Lipids; Liver; Measurement; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Methods; Modeling; Mus; Muscle; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Organ; PTGS2 gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Plasminogen Activator Inhibitor 1; Production; Proteins; Research Personnel; Rodent; Rodent Model; Role; Scanning; Signal Transduction; Signaling Protein; Site; Small Interfering RNA; TNFRSF5 gene; TRAF6 gene; Technology; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; Transgenic Organisms; Triglycerides; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Ubiquitin; Ubiquitination; Up-Regulation; cytokine; human TNF protein; improved; in vivo; inflammatory marker; inhibitor/antagonist; insulin sensitivity; insulin signaling; interest; programs; protein degradation; research study; resistin; salicylate; sperm acrosomal antigen 1; transcription factor

DESCRIPTION (provided by applicant): The previous cycle of this grant hypothesized a critical role for the inflammatory IKKbeta/NF-kappaB pathway in the pathogenesis of obesity- and diet-induced insulin resistance. We now know that the pathway is activated in fat and liver by obesity and high fat diet (HFD) and that activation of NF-kappaB in fat and liver causes insulin resistance, at least in part due to the production of proinflammatory cytokines (IL-6, resistin, IL-1beta, TNF-alpha). Inhibition of IKKbeta and NF-kappaB, either genetically or pharmacologically, and cytokine neutralization reverse insulin resistance in animals and/or humans. Elevations in inflammatory markers that are seen in patients are readily reproduced in rodent models dietary and genetically induced insulin resistance. These are reversed in both rodents and humans in parallel with improvements in insulin resistance and dramatic reductions in triglyceride, free fatty acid and glucose levels. To continue developing and testing these hypotheses, we now propose a comprehensive plan to identify intracellular proteins that modulate NF-kappaB signaling and insulin resistance. In addition to the cytokines listed above, other NF-kappaB targets induced by HFD and obesity in fat and liver are associated with the metabolic syndrome and atherosclerosis (CRP, PAI-1, SAA-1, VCAM1, ICAM1, iNOS and COX2). As the subject of this proposal we also see constitutive, NF-kappaB dependent expression of A20, IKKi/epsilon, and IkappaBzeta, in fat and liver of obese/HFD rodent models. These normally inducible regulators and/or mediators of NF-kappaB signaling have intriguing functions in host defense. We plan to determine if they also function in insulin resistance. A20 induction limits NF-kappaB signaling by altering the ubiquitination of upstream signaling proteins; NF-kappaB induces the expression of IKKi/epsilon, a Ser/Thr kinase that inhibits insulin signaling; and IkappaBzeta, unlike IkappaBalpha, selectively increases expression of a few interesting NF-kappaB targets such as IL-6. Experiments presented in this application determine the in vivo roles of these proteins in fat and liver, delving further into the mechanisms of HFD/obesity-induced insulin resistance by looking both at tissue-specific effects and inter-organ cross-talk. The findings will improve our understanding of the role of subacute 'inflammation' in insulin resistance, T2D and the metabolic syndrome, and may identify new and more selective targets for therapeutic intervention.

描述（由申请人提供）：该资助的前一个周期假设炎症性IKK β/NF-κ B通路在肥胖和饮食诱导的胰岛素抵抗的发病机制中起关键作用。我们现在知道，肥胖和高脂饮食（HFD）激活了脂肪和肝脏中的这一通路，脂肪和肝脏中NF-κ B的激活导致胰岛素抵抗，至少部分原因是促炎细胞因子（IL-6，IFN-γ，IL-1 β，TNF-α）的产生。IKK β和NF-κ B的抑制，无论是遗传性的还是非遗传性的，以及细胞因子中和逆转动物和/或人类的胰岛素抵抗。在啮齿动物模型中，饮食和遗传诱导的胰岛素抵抗很容易再现患者中观察到的炎症标志物升高。这些在啮齿动物和人类中逆转，同时改善胰岛素抵抗和显著降低甘油三酯、游离脂肪酸和葡萄糖水平。为了继续发展和测试这些假设，我们现在提出了一个全面的计划，以确定细胞内的蛋白质，调节NF-κ B信号和胰岛素抵抗。除了上面列出的细胞因子之外，由HFD和脂肪和肝脏中的肥胖诱导的其他NF-κ B靶标与代谢综合征和动脉粥样硬化相关（CRP、派-1、SAA-1、VCAM 1、ICAM 1、iNOS和COX 2）。作为该提议的主题，我们还在肥胖/HFD啮齿动物模型的脂肪和肝脏中观察到A20、IKKi/IKK β和IkappaBzeta的组成型、NF-κ B依赖性表达。这些正常诱导的调节因子和/或NF-κ B信号传导介质在宿主防御中具有有趣的功能。我们计划确定它们是否也在胰岛素抵抗中起作用。A20诱导通过改变上游信号传导蛋白的泛素化限制NF-κ B信号传导; NF-κ B诱导IKKi/IKK的表达，IKKi/IKK是一种抑制胰岛素信号传导的Ser/Thr激酶;与IkappaB α不同，IkappaB zeta选择性地增加一些感兴趣的NF-κ B靶点如IL-6的表达。本申请中提出的实验确定了这些蛋白质在脂肪和肝脏中的体内作用，通过观察组织特异性效应和器官间串扰，进一步深入研究了HFD/肥胖诱导的胰岛素抵抗的机制。这些发现将提高我们对亚急性“炎症”在胰岛素抵抗，T2 D和代谢综合征中的作用的理解，并可能为治疗干预确定新的更具选择性的靶点。