Metabolic stress signaling

 描述（由申请人提供）：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，其特征在于胰岛素抵抗和高血糖症，其可导致β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。我们已经确定了PPARα通路是肝脏JNK信号传导的主要靶点，通过调节肝细胞因子成纤维细胞生长因子21（FGF 21）的表达，促进HFD诱导的胰岛素抵抗。我们已经证明，由喂食HFD引起的JNK激活有效抑制了PPARα活性。因此，肝脏JNK活性的破坏导致HFD喂养小鼠的肝脏PPARα活性增加，血液中循环的FGF 21量增加，并改善肝脏功能。Fgf 21表达的破坏阻止了JNK抑制的作用以引起改善的炎症。基于这些数据，我们提出，PPARα/FGF 21轴介导了肝脏JNK对胰岛素敏感性的影响。本研究项目的总体目标是检验以下假设：PPARα/FGF 21轴通过肝脏JNK参与代谢应激信号传导。我们将研究JNK介导的抑制PPARα活性的机制。我们还将检测PPARα靶基因Fgf 21作为JNK调节的胰岛素抵抗的介体的作用。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。

 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.