Adipose Tissue Metabolic Stress Responses

项目摘要 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，以胰岛素抵抗和高血糖为特征，可导致B 细胞功能障碍和2型糖尿病因此，重要的是我们要了解 和肥胖发展的病理生理学，因为这些知识代表了设计的基础， 潜在的治疗干预。 cJun NH 2-末端激酶（JNK）信号通路在应激反应中起作用，包括代谢 高脂肪饮食（HFD）引起的压力。重要的是，使用小鼠进行的功能丧失研究表明， 脂肪细胞中JNK 1和JNK 2的缺乏可以防止脂肪组织炎症和 全身性胰岛素抵抗然而，在脂肪细胞中介导JNK信号传导作用的机制 不清楚。 我们将集中研究两个问题： a）JNK的生理相关形式是什么，它驱动脂肪组织炎症和胰岛素 抵抗？脂肪细胞表达两种编码JNK的基因（Mapk 8和Mapk 9编码JNK 1和JNK 2， 两个基因的转录物通过相互排斥地包含外显子7a而被选择性剪接 及7 b。这些替代外显子编码底物结合位点的片段。JNK 17 a和JNK 27 a展品 类似的底物特异性不同于JNK 17 b和JNK 27 b的类似底物偏好。我们将 确定这些JNK剪接体中的哪一种介导JNK对脂肪组织炎症的作用， 全身性胰岛素抵抗 B）什么机制介导脂肪细胞JNK的作用？已经提出JNK对 炎症可能是由脂肪细胞IL 6表达增加介导的，JNK对全身炎症的影响可能是通过增加脂肪细胞IL 6表达来介导的。 胰岛素抵抗可能由FGF 21表达降低介导。一个严格的测试的充分性， 这些JNK介导的对脂肪因子表达的作用需要证实这些JNK的作用。 反应性脂肪因子，并确定是否有JNK信号传导的其他目标。 这项研究计划的总体目标是确定JNK功能的分子机制， 脂肪细胞这一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新的识别 导致肥胖反应的机制。这些知识可以代表设计的基础， 用于治疗代谢综合征和2型糖尿病的新治疗策略。

Project Summary 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. The cJun NH2-terminal kinase (JNK) signaling pathway functions during stress responses, including metabolic stress caused by feeding a high fat diet (HFD). Importantly, loss-of-function studies using mice demonstrate that deficiency of JNK1 plus JNK2 in adipocytes prevents adipose tissue inflammation and the development of systemic insulin resistance. However, the mechanisms that mediate the actions of JNK signaling in adipocytes are unclear. We will focus our studies on two questions: a) What is the physiologically relevant form of JNK that drives adipose tissue inflammation and insulin resistance? Adipocytes express two genes that encode JNK (Mapk8 & Mapk9 encode JNK1 & JNK2, respectively) and transcripts of both genes are alternatively spliced by mutually exclusive inclusion of exons 7a & 7b. These alternative exons encode a segment of the substrate binding site. The JNK17a & JNK27a exhibit similar substrate specificities that differ from the similar substrate preferences of JNK17b & JNK27b. We will determine which of these JNK spliceoforms mediates effects of JNK on adipose tissue inflammation and systemic insulin resistance. b) What mechanism mediates the actions of adipocyte JNK? It has been proposed that the effects of JNK on inflammation may be mediated by increased adipocyte IL6 expression and that the effects of JNK on systemic insulin resistance may be mediated by decreased FGF21 expression. A rigorous test of the sufficiency of these JNK-mediated actions on adipokine expression is required to confirm the actions of these JNK- responsive adipokines and to identify whether there are additional targets of JNK signaling. The overall goal of this research program is to identify molecular mechanisms that account for JNK function in adipocytes. Achievement of this goal 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.