Regulation of lipolysis by mTORC1

mTORC1 对脂肪分解的调节

基本信息

批准号：
9222006
负责人：
Konstantin V Kandror
金额：
$ 38.69万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-10 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222006
关键词：
Address Adipocytes Adipose tissue Animal Model Cells Complex Defect Developed Countries Developing Countries Diabesity Diabetes Mellitus Doxycycline Drosophila genus Enzymes Epidemic Evolution FRAP1 gene Failure Fatty Acids Fatty Liver Fatty acid glycerol esters Generations Genetic Screening Genetic Transcription Growth Health Health Care Costs Heart Heart Diseases Hormones Hypertension In Vitro Insulin Insulin Resistance Knowledge Lead Life Expectancy Lipase Lipids Lipolysis Liver Liver diseases Longevity Mammalian Cell Mammals Mediating Messenger RNA Metabolic Metabolic Control Metabolic Diseases Modality Modeling Molecular Myocardial dysfunction Non obese Non-Insulin-Dependent Diabetes Mellitus Nuclear Nutrient Obesity Organ Organism Overnutrition Pancreas Pathologic Physiological Play Protein Biosynthesis Proteins Quality of life Regulation Regulatory Pathway Research Resources Role Saccharomyces cerevisiae Skeletal Muscle Societies Testing Tissues Transgenic Mice Translations Triglycerides United States Yeasts base cell growth fight against fitness global health improved in vivo insulin signaling lipid metabolism mouse model novel prevent promoter public health relevance response sensor transcription factor

项目摘要

DESCRIPTION (provided by applicant): Abnormal lipid storage and partitioning is one of the top global health problems because it represents a major (or the major) causative factor of insulin resistance, type 2 diabetes, hypertension, heart and liver disease, etc. In a healthy non-obese organism, lipids are, for the most part, stored in adipose tissue as triglycerides (TG). Redistribution of TG from adipocytes to non-adipose tissues, such as skeletal muscle, heart, liver and pancreas triggers a number of pathological effects collectively known as lipotoxicity that causes and aggravates insulin resistance, type 2 diabetes, and other metabolic disease. Mammalian target of rapamycin complex 1 (mTORC1) has been established as the central controller of protein biosynthesis and cell growth. In addition, mTORC1 is now emerging as an important regulator of lipid metabolism. In particular, we have recently found that mTORC1 suppresses lipolysis by inhibiting expression of the rate-limiting lipolytic enzyme, adipose triglyceride lipase thus rendering lipolysis responsive to regulation by insulin and nutrients. Using a genetic screen in S.cerevisiae, we have determined that the effect of mTORC1 on the expression of ATGL is mediated by the primary early growth response transcription factor Egr1. However, we still do not know how exactly mTORC1 activates expression of Egr1 in mammalian cells. Therefore, in Specific Aim 1, we will explore the molecular mechanism of Egr1 regulation by mTORC1 in adipocytes. In Specific Aim 2, we will test the hypothesis that FSP27 (a.k.a. CIDEC) plays a dual role in fat metabolism as a lipid droplet protein and a co-factor of Egr1 that regulates ATGL transcription. In Specific Aim 3, we will use a newly developed model of conditional fat-specific constitutively active Rheb transgenic mouse in order to test the hypothesis that mTORC1 in adipocytes is responsible for lipid partitioning and metabolic fitness in vivo.

描述（由申请人提供）：异常的脂质储存和分配是全球最重要的健康问题之一，因为它是胰岛素抵抗、2型糖尿病、高血压、心脏病和肝脏疾病等的主要（或主要）致病因素。作为健康的非肥胖生物体，脂质大部分以甘油三酯 (TG) 的形式储存在脂肪组织中。TG 从脂肪细胞重新分配到非脂肪组织，例如骨骼。肌肉、心脏、肝脏和胰腺会引发一系列统称为脂毒性的病理效应，导致和加重胰岛素抵抗、2 型糖尿病和其他代谢疾病，哺乳动物雷帕霉素靶点复合物 1 (mTORC1) 已被确定为脂肪毒性的中央控制器。此外，mTORC1 现在正在成为脂质代谢的重要调节剂，特别是，我们最近发现 mTORC1 通过抑制脂肪分解。通过在酿酒酵母中进行遗传筛选，我们确定 mTORC1 对 ATGL 表达的影响是由初级介导的。早期生长反应转录因子 Egr1 然而，我们仍然不知道 mTORC1 究竟如何激活哺乳动物细胞中的 Egr1 表达，因此，在特定目标 1 中，我们将。探索脂肪细胞中 mTORC1 调节 Egr1 的分子机制。在特定目标 2 中，我们将检验 FSP27（又名 CIDEC）作为脂滴蛋白和调节 ATGL 的 Egr1 辅助因子在脂肪代谢中发挥双重作用的假设。在特定目标 3 中，我们将使用新开发的条件性脂肪特异性组成型活性 Rheb 转基因小鼠模型来检验以下假设：脂肪细胞中的 mTORC1 负责体内脂质分配和代谢适应性。