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全球性健康问题。肥胖的一个后果是 代谢综合征的发展，其特征是胰岛素抵抗和高血糖症，可导致b细胞功能障碍和2型糖尿病。因此，重要的是，我们获得的生理学和病理生理学的发展肥胖的理解，因为这方面的知识代表了潜在的治疗干预措施的设计基础。最近的研究已经确定cJun NH 2-末端激酶（JNK）信号转导途径作为代谢应激反应的介体。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的发展中起着重要作用。相比之下，外周组织中的JNK可引起胰岛素抵抗而不改变肥胖。由喂食HFD引起的JNK依赖性胰岛素抵抗的机制尚未确定。本研究计划的重点是肝脏JNK信号转导的代谢功能。在研究支持的最初阶段，我们将PPARa途径确定为肝JNK信号传导的主要靶点，其有助于HFD诱导的胰岛素抵抗。我们证明了由喂食HFD引起的JNK激活有效地抑制了PPARa活性。PPARa介导的肝基因表达的关键靶标是肝细胞因子成纤维细胞生长因子21（FGF 21）。因此，肝脏中JNK信号传导的破坏导致肝脏PPARa活性增加，血液中循环的FGF 21的量增加，以及HFD喂养的小鼠中的肝脏功能改善。肝Fgf 21表达的破坏阻止JNK缺乏的影响，导致改善的肝纤维化。因此，PPARa/FGF 21轴代表促进全身胰岛素敏感性的肝JNK信号传导的主要靶标。这项研究计划的总体目标是确定肝脏JNK信号转导机制，有助于调节胰岛素敏感性。我们的分析确立了肝PPARa的关键作用。然而，介导JNK对PPARa作用的分子靶标尚未确定。分子机制的鉴定是本次更新申请的重点。实现这一建议的目标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。