Metabolic stress signaling

 描述(申请人提供)：人类肥胖是一个严重的世界性健康问题。肥胖的一个后果是发展出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。我们已经确定PPARα通路是肝脏JNK信号转导的主要靶点，通过调节肝细胞因子成纤维细胞生长因子21(FGF21)的表达，参与高脂饮食诱导的胰岛素抵抗。我们已经证明，由饲喂高脂饲料引起的JNK激活有效地抑制了PPARα活性。因此，破坏肝脏JNK活性会导致肝脏PPARα活性增加，血液中循环的FGF21量增加，并改善高脂饲料喂养的小鼠的血糖。阻断FGF21的表达可以阻止JNK抑制导致血糖改善的效果。基于这些数据，我们认为PPARα/FGF21轴介导了肝脏JNK对胰岛素敏感性的影响。本研究的总体目标是验证PPARα/FGF21轴通过肝脏jnk参与代谢应激信号的假设。我们将研究JNK介导的抑制PPARα活性的机制。我们还将测试PPARα靶基因FGF21在JNK调节的胰岛素抵抗中的作用。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。

 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.