Metabolic Stress Signaling

代谢应激信号

• 批准号: 10437020
• 负责人: Roger J Davis
• 金额: $ 52.78万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437020
• 关键词: Achievement; B-Lymphocytes; Blood; Development; Energy Metabolism; Functional disorder; Gene Expression; Genomics; Goals; Health; Hepatic; High Fat Diet; Human; Hyperglycemia; Insulin Resistance; Knockout Mice; Knowledge; Lead; Liver; MAPK8 gene; Mediating; Mediator of activation protein; Metabolic; Metabolic stress; Metabolic syndrome; Molecular; Molecular Target; Mus; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peripheral; Phosphorylation; Phosphotransferases; Physiological; Physiology; Protein Isoforms; Proteins; Regulation; Research; Research Support; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Testing; Therapeutic Intervention; Tissues; biological adaptation to stress; design; feeding; fibroblast growth factor 21; improved; insulin regulation; insulin sensitivity; novel therapeutic intervention; obesity development; phosphoproteomics; prevent; programs; response; treatment strategy

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 b-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. This research program is focused on the metabolic function of hepatic JNK signaling. During the initial period of research support, we identified the PPARa pathway as a major target of hepatic JNK signaling that contributes to HFD-induced insulin resistance. We demonstrated that JNK activation caused by feeding a HFD potently suppresses PPARa activity. A key target of PPARa -mediated hepatic gene expression is the hepatokine fibroblast growth factor 21 (FGF21). Consequently, disruption of JNK signaling in the liver causes increased hepatic PPARa activity, increased amounts of FGF21 circulating in the blood, and improved glycemia in HFD-fed mice. Disruption of hepatic Fgf21 expression prevents the effects of JNK deficiency to cause improved glycemia. The PPARa/FGF21 axis therefore represents a major target of hepatic JNK signaling that promotes systemic insulin sensitivity. The overall goal of this research program is to identify mechanisms of hepatic JNK signaling that contribute to the regulation of insulin sensitivity. Our analysis establishes a key role for hepatic PPARa. However, the molecular target(s) that mediate the effects of JNK on PPARa have not been established. The identification of molecular mechanism is the focus of this renewal application. 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.

人类肥胖代表了一个严重的全球健康问题。肥胖的结果之一是 代谢综合征的发展，其特征是胰岛素抵抗和高血糖，可能导致B细胞功能障碍和2型糖尿病。因此，重要的是我们了解肥胖发展的生理学和病理生理学，因为这种知识代表了设计潜在治疗干预措施的基础。最近的研究已经确定CJUN NH2-末端激酶（JNK）信号转导途径是代谢应激反应的介体。喂养高脂肪饮食（HFD）会增加JNK活性，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在能量消耗和肥胖的发展中的核心作用。相反，外周组织中的JNK会导致胰岛素抵抗，而不会改变肥胖。尚未定义由喂养HFD引起的JNK依赖性胰岛素抵抗的机制。该研究计划的重点是肝JNK信号的代谢功能。在研究的最初阶段，我们将PPARA途径确定为有助于HFD诱导的胰岛素耐药性的肝JNK信号传导的主要目标。我们证明，通过喂养HFD引起的JNK激活有效抑制PPARA活性。 PPARA介导的肝基因表达的关键靶标是肝素成纤维细胞生长因子21（FGF21）。因此，肝脏中JNK信号传导的破坏会增加肝PPARA活性，增加血液中循环的FGF21的量增加，并改善了HFD喂养小鼠的血糖。肝FGF21表达的破坏阻止了JNK缺乏的影响，从而导致血糖​​改善。因此，PPARA/FGF21轴代表了肝JNK信号的主要目标，该肝JNK信号传导促进了全身性胰岛素敏感性。该研究计划的总体目标是确定有助于调节胰岛素敏感性的肝JNK信号的机制。我们的分析确立了肝PPARA的关键作用。但是，尚未建立介导JNK对PPARA影响的分子靶标。分子机制的鉴定是这种更新应用的重点。实现该提案的目标将增加对分子对肥胖反应的理解。我们预计该研究计划的成功完成将导致识别有助于肥胖反应的新机制。这些知识可能代表了设计新型治疗策略的基础，用于治疗代谢综合征和2型糖尿病。