Metabolic Stress Signaling

代谢应激信号

• 批准号: 10119846
• 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/10119846
• 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 therapeutics; 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.

人类肥胖是一个严重的世界性健康问题。肥胖的一个后果是 以胰岛素抵抗和高血糖为特征的代谢综合征的发展，可导致b细胞功能障碍和2型糖尿病。因此，我们必须了解肥胖发生的生理学和病理生理学，因为这些知识是设计潜在的治疗干预措施的基础。最近的研究发现，cJun NH2末端激酶(JNK)信号转导通路是代谢应激反应的中介。喂食高脂肪饮食(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症的发展中发挥着核心作用。相比之下，外周组织中的JNK可以在不改变肥胖的情况下导致胰岛素抵抗。喂养高脂饲料引起的JNK依赖型胰岛素抵抗的机制尚未明确。本研究的重点是肝脏JNK信号的代谢功能。在研究支持的最初阶段，我们发现PPARa通路是肝脏JNK信号转导的一个主要靶点，参与了HFD诱导的胰岛素抵抗。我们证明了由饲喂HFD引起的JNK激活有效地抑制了PPARa活性。PPARa介导的肝脏基因表达的一个关键靶点是肝细胞因子成纤维细胞生长因子21(FGF21)。因此，肝脏中JNK信号的中断导致肝脏PPARa活性增加，血液中循环的FGF21数量增加，并改善高脂饲料喂养的小鼠的血糖。阻断肝脏FGF21的表达可阻止JNK缺乏症引起的血糖改善。因此，PPARa/FGF21轴是肝脏JNK信号的主要靶点，促进全身性胰岛素敏感性。该研究计划的总体目标是确定肝脏JNK信号调节胰岛素敏感性的机制。我们的分析确定了肝脏PPARa的关键作用。然而，介导JNK对PPARa影响的分子靶点(S)尚未建立。分子机理的识别是这一更新应用的重点。这项提案的目标的实现将增加对肥胖分子反应的理解。我们预计，这项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。这些知识可能是设计治疗代谢综合征和2型糖尿病的新治疗策略的基础。