Adipose Tissue Metabolic Stress Responses

脂肪组织代谢应激反应

• 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
• 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

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.

项目摘要 人类肥胖代表了一个严重的全球健康问题。肥胖的结果之一是 代谢综合征的发展，其特征是胰岛素抵抗和高血糖，可能导致B 细胞功能障碍和2型糖尿病。因此，重要的是要了解生理学 和肥胖发展的病理生理学，因为这种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）信号通路在应力反应过程中起作用，包括代谢 喂养高脂饮食（HFD）引起的压力。重要的是，使用小鼠的功能丧失研究表明 脂肪细胞中JNK1加JNK2的缺乏可防止脂肪组织炎症和发展 全身性胰岛素抵抗。但是，介导脂肪细胞中JNK信号的作用的机制 不清楚。 我们将把研究重点放在两个问题上： 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＆MAPK9编码JNK1＆JNK2， 分别通过互斥外显子7a互斥两个基因的转录本。 ＆7b。这些替代外显子编码底物结合位点的段。 JNK17A和JNK27A展览 与JNK17B和JNK27B的相似底物偏好不同的类似底物特异性。我们将 确定这些JNK剪接体中的哪一个介导了JNK对脂肪组织炎症的影响 全身性胰岛素抵抗。 b）什么机制介导了脂肪细胞JNK的作用？有人提出JNK对 炎症可能是通过脂肪细胞IL6表达增加而介导的，而JNK对全身性的影响 胰岛素抵抗可以通过降低FGF21表达介导。严格测试足够 这些JNK介导的对脂肪因子表达的作用需要确认这些JNK-的作用 响应脂肪因子并确定JNK信号是否还有其他目标。 该研究计划的总体目标是确定解释JNK功能的分子机制 脂肪细胞。实现这一目标将增加对分子对肥胖反应的理解。我们 预计该研究计划的成功完成将导致新的识别 有助于肥胖反应的机制。这些知识可能代表设计的基础 用于治疗代谢综合征和2型糖尿病的新型治疗策略。