Adipose Tissue Metabolic Stress Responses

脂肪组织代谢应激反应

基本信息

批准号：
10516801
负责人：
Roger J Davis
金额：
$ 58.12万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-17 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10516801
关键词：
Achievement Address Adipocytes Adipose tissue Alternative Splicing Amino Acid Sequence Amino Acids B-Lymphocytes Binding Sites Development Exhibits Exons FGF21 gene Functional disorder Genes Goals Health High Fat Diet Human Hyperglycemia IL6 gene Inflammation Insulin Resistance Investigation Knowledge Lead MAPK8 gene MAPK9 gene Mediating Messenger RNA Metabolic stress Metabolic syndrome Molecular Mus N-terminal Non-Insulin-Dependent Diabetes Mellitus Obesity Phosphotransferases Physiological Physiology Protein Isoforms Protein Kinase Research Role Signal Pathway Signal Transduction Stress Substrate Specificity Testing Text Therapeutic Intervention Transcript adipokines biological adaptation to stress design feeding insight loss of function novel therapeutic intervention obesity development preference prevent programs response treatment strategy

项目摘要

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.

项目概要人类肥胖是一个严重的世界性健康问题。肥胖的后果之一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，了解生理学非常重要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措施。 cJun NH2 末端激酶 (JNK) 信号通路在应激反应期间发挥作用，包括代谢高脂肪饮食 (HFD) 造成的压力。重要的是，使用小鼠进行的功能丧失研究表明脂肪细胞中 JNK1 和 JNK2 的缺乏可防止脂肪组织炎症和脂肪组织的发展全身性胰岛素抵抗。然而，介导脂肪细胞中 JNK 信号传导作用的机制不清楚。我们将重点研究两个问题： a) 驱动脂肪组织炎症和胰岛素的 JNK 的生理相关形式是什么反抗？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物通过互斥包含外显子 7a 进行选择性剪接 & 7b.这些替代外显子编码底物结合位点的片段。 JNK17a 和 JNK27a 展览相似的底物特异性不同于 JNK17b 和 JNK27b 的相似底物偏好。我们将确定这些 JNK 剪接形式中的哪一个介导 JNK 对脂肪组织炎症的影响，以及全身性胰岛素抵抗。 b) 什么机制介导脂肪细胞JNK 的作用？有人提出，JNK 对炎症可能是由脂肪细胞 IL6 表达增加介导的，并且 JNK 对全身系统的影响胰岛素抵抗可能是由 FGF21 表达减少介导的。充分性的严格测试需要这些 JNK 介导的脂肪因子表达作用来确认这些 JNK 的作用反应性脂肪因子并确定是否存在 JNK 信号传导的其他靶标。该研究项目的总体目标是确定 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。我们预计该研究计划的成功完成将导致新的发现有助于肥胖反应的机制。这些知识可以代表设计的基础治疗代谢综合征和2型糖尿病的新治疗策略。