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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.

项目总结