Adipose Tissue Metabolic Stress Responses

项目摘要 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，重要的是我们要对生理学有所了解 以及肥胖发展的病理生理学，因为这些知识代表了设计的基础 潜在的治疗干预措施。 CJun NH2末端激酶(JNK)信号通路在包括代谢在内的应激反应中发挥作用 由喂食高脂肪饮食(HFD)引起的压力。重要的是，用小鼠进行的功能丧失研究表明 脂肪细胞中JNK1和JNK2的缺失可阻止脂肪组织炎症和糖尿病的发生。 全身性胰岛素抵抗。然而，在脂肪细胞中介导JNK信号作用的机制 都不清楚。 我们将重点研究两个问题： A)推动脂肪组织炎症和胰岛素的生理上相关的JNK形式是什么 抵抗？脂肪细胞表达两个编码JNK的基因(Mapk8和Mapk9编码JNK1和JNK2， 分别)，并且两个基因的转录本通过相互排斥地包含外显子7a来交替地剪接 &7b。这些可选择的外显子编码底物结合位点的一段。JNK17a和JNK27a展品 类似的底物特性，不同于JNK17b和JNK27b相似的底物偏好。我们会 确定这些JNK剪接体中的哪一种介导JNK对脂肪组织炎症和 全身性胰岛素抵抗。 B)脂肪细胞JNK的作用机制是什么？有人提出，JNK对 炎症可能通过脂肪细胞IL6表达增加而介导，JNK对全身炎症反应的影响 胰岛素抵抗可能是通过降低FGF21的表达来实现的。对……充分性的严格检验 这些JNK介导的对脂肪因子表达的作用需要确认这些JNK- 以确定是否存在JNK信号转导的其他靶点。 本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 预计本研究计划的成功完成将导致确定新的 导致肥胖反应的机制。这些知识可以作为设计的基础 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.