Metabolic stress signaling

代谢应激信号

• 批准号: 9128103
• 负责人: Roger J Davis
• 金额: $ 37.69万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128103
• 关键词: Accounting; Achievement; Beta Cell; Blood; Data; Development; Energy Metabolism; Functional disorder; Gene Targeting; Genomics; Goals; Health; Hepatic; High Fat Diet; Human; Hyperglycemia; Insulin Resistance; JNK-activating protein kinase; Knockout Mice; Knowledge; Lead; Liver; MAPK8 gene; Mediating; Mediator of activation protein; Metabolic stress; Metabolic syndrome; Molecular; Mus; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR alpha; Pathway interactions; Peripheral; Physiological; Physiology; Proteins; Regulation; Repression; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Testing; Therapeutic Intervention; Tissues; base; biological adaptation to stress; design; feeding; fibroblast growth factor 21; improved; insulin sensitivity; novel therapeutics; phosphoproteomics; prevent; programs; public health relevance; response; treatment strategy

 DESCRIPTION (provided by applicant): Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of metabolic syndrome, characterized by insulin resistance and hyperglycemia, that can lead to β cell dysfunction and type 2 diabetes. It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity because this knowledge represents a basis for the design of potential therapeutic interventions. Recent studies have identified the cJun NH2-terminal kinase (JNK) signal transduction pathway as a mediator of metabolic stress responses. Feeding a high fat diet (HFD) causes increased JNK activity and promotes both obesity and insulin resistance. Studies using tissue-specific knockout mice demonstrate a central role for JNK in the regulation of energy expenditure and the development of obesity. In contrast, JNK in peripheral tissues can cause insulin resistance without changes in obesity. The mechanism that accounts for JNK- dependent insulin resistance caused by feeding a HFD has not been defined. We have identified the PPARα pathway as a major target of hepatic JNK signaling that contributes to HFD- induced insulin resistance by regulating the expression of the hepatokine fibroblast growth factor 21 (FGF21). We have demonstrated that JNK activation caused by feeding a HFD potently suppresses PPARα activity. Consequently, disruption of hepatic JNK activity causes increased hepatic PPARα activity, increased amounts of FGF21 circulating in the blood, and improved glycemia in HFD-fed mice. Disruption of Fgf21 expression prevents the effects of JNK inhibition to cause improved glycemia. Based on these data, we propose that the PPARα/FGF21 axis mediates the effects of hepatic JNK on insulin sensitivity. The overall goal of this research program is to test the hypothesis that the PPARα/FGF21 axis contributes to metabolic stress signaling by hepatic JNK. We will examine the mechanism of JNK-mediated repression of PPARα activity. We will also test the role of the PPARα target gene Fgf21 as a mediator of JNK-regulated insulin resistance. Achievement of the goals of this proposal will increase understanding of the molecular response to obesity. We anticipate that the successful completion of this research program will lead to the identification of new mechanisms that contribute to the obesity response. This knowledge may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type 2 diabetes.

 描述（由申请人提供）：人类肥胖是一个严重的世界性健康问题。肥胖的后果之一是产生以胰岛素抵抗和高血糖为特征的代谢综合征，这可能导致 β 细胞功能障碍和 2 型糖尿病。因此，我们了解肥胖发展的生理学和病理生理学非常重要，因为这些知识是设计潜在治疗干预措施的基础。最近的研究已确定 cJun NH2 末端激酶 (JNK) 信号转导途径是代谢应激反应的介质。高脂肪饮食 (HFD) 会导致 JNK 活性增加，并促进肥胖和胰岛素抵抗。使用组织特异性基因敲除小鼠的研究表明，JNK 在调节能量消耗和肥胖发展中发挥着核心作用。相比之下，外周组织中的JNK可引起胰岛素抵抗，而不会改变肥胖状况。因喂养 HFD 引起的 JNK 依赖性胰岛素抵抗的机制尚未明确。我们已经确定 PPARα 通路是肝脏 JNK 信号传导的主要靶标，通过调节肝因子成纤维细胞生长因子 21 (FGF21) 的表达，有助于 HFD 诱导的胰岛素抵抗。我们已经证明，喂食 HFD 引起的 JNK 激活可有效抑制 PPARα 活性。因此，肝脏 JNK 活性的破坏会导致肝脏 PPARα 活性增加，血液中循环的 FGF21 量增加，并改善 HFD 喂养小鼠的血糖。 Fgf21 表达的破坏可防止 JNK 抑制作用改善血糖。基于这些数据，我们提出 PPARα/FGF21 轴介导肝脏 JNK 对胰岛素敏感性的影响。该研究计划的总体目标是检验 PPARα/FGF21 轴通过肝脏 JNK 促进代谢应激信号传导的假设。我们将研究 JNK 介导的 PPARα 活性抑制机制。我们还将测试 PPARα 靶基因 Fgf21 作为 JNK 调节的胰岛素抵抗介质的作用。该提案目标的实现将增加对肥胖分子反应的理解。我们预计该研究计划的成功完成将导致发现有助于肥胖反应的新机制。这些知识可能为设计治疗代谢综合征和 2 型糖尿病的新治疗策略奠定基础。