Regulation of lipolysis by mTORC1

mTORC1 对脂肪分解的调节

基本信息

批准号：
8240726
负责人：
Konstantin V Kandror
金额：
$ 20.44万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8240726
关键词：
Ablation Adipocytes Adverse drug effect Affect Aging Animals Blood Cardiovascular Diseases Catabolism Commit Cyclic AMP Data Development Diabetes Mellitus Diet Drosophila genus Dyslipidemias Elderly Enzymes Evolution Family Fatty acid glycerol esters Genetic Genetic Transcription Growth Hamartoma Health Health Care Costs Heart Homeostasis Homologous Gene Hormones Human Insulin Resistance Investigation Kidney Lead Lesion Life Expectancy Link Lipolysis Liver Longevity Mammalian Cell Mediating Medicare Metabolic Metabolic Diseases Modality Molecular Molecular Target Mus Muscle Cells Muscle Fibers Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Pathway interactions Phenotype Physiological Physiology Play Population Printing Process Production Protein-Serine-Threonine Kinases Publications Publishing Quality of life Raptors Regulation Regulatory Pathway Reporting Resources Risk Role Saccharomyces cerevisiae Screening Result Signal Transduction Societies Source Tissues Triglycerides Work age related aged aging population healthy aging human FRAP1 protein improved inhibitor/antagonist knock-down lipid metabolism novel programs protein complex response sensor transcription factor trend

项目摘要

DESCRIPTION (provided by applicant): Impaired lipolysis and dysregulated levels of circulating free fatty acids represent important causative factors for the development of insulin resistance, type 2 diabetes, cardiovascular disease and other hazardous metabolic conditions that rapidly advance and pose especially serious health risk in the elderly. Restraining metabolic diseases in the aging population will improve life quality as well as life expectancy and radically reduce health care costs. We have recently found that activation of mTORC1 inhibits expression of the rate-limiting lipolytic enzyme, ATGL, suppresses basal and cAMP-stimulated lipolysis, and causes marked accumulation of triglycerides in fat and muscle cells. Inhibition of mTORC1 has the opposite effect. In order to determine the molecular mechanism of mTORC1 action, we have conducted a screen in S. cerevisiae. Results of this screen suggest that mTORC1 inhibits ATGL expression via transcription factors of the early growth response (Egr) family. Thus, in Specific Aim 1 we propose to mechanistically establish the role of Egr1/2 in mTORC1- mediated transcription of ATGL and lipolysis, and in Specific Aim 2 we will investigate the role of the mTORC1/Egr1/2 axis in the metabolic disease and aging. We believe that our work will help to establish the mTORC1-mediated pathway as a central controller of FFA homeostasis and dysregulation of this pathway - as a major etiological factor of metabolic disease that limit healthspan and lifespan of the US population. PUBLIC HEALTH RELEVANCE: Dysregulation of lipolysis in fat tissue represents a major causative factor for the development of cardiovascular disease, insulin resistance, and other age-related hazardous metabolic conditions. We have recently found that the mTORC1-mediated pathway controls lipolysis in adipocytes, and we propose to determine the molecular mechanism and the physiological significance of our observations.

描述（由申请人提供）：脂肪分解受损和循环游离脂肪酸水平失调是胰岛素抵抗、2 型糖尿病、心血管疾病和其他危险代谢病症发展的重要致病因素，这些病症迅速进展并在人类中造成特别严重的健康风险。老年。抑制老龄化人口中的代谢性疾病将提高生活质量和预期寿命，并从根本上降低医疗保健成本。我们最近发现，mTORC1 的激活会抑制限速脂肪分解酶 ATGL 的表达，抑制基础脂肪分解和 cAMP 刺激的脂肪分解，并导致脂肪和肌肉细胞中甘油三酯的显着积累。抑制 mTORC1 会产生相反的效果。为了确定 mTORC1 作用的分子机制，我们在酿酒酵母中进行了筛选。该筛选结果表明 mTORC1 通过早期生长反应 (Egr) 家族的转录因子抑制 ATGL 表达。因此，在具体目标 1 中，我们建议从机制上确定 Egr1/2 在 mTORC1 介导的 ATGL 转录和脂肪分解中的作用，在具体目标 2 中，我们将研究 mTORC1/Egr1/2 轴在代谢疾病和脂肪分解中的作用。老化。我们相信，我们的工作将有助于建立 mTORC1 介导的通路作为 FFA 稳态和该通路失调的中央控制器 - 作为限制美国人口健康寿命和寿命的代谢疾病的主要病因。公共健康相关性：脂肪组织中的脂解失调是心血管疾病、胰岛素抵抗和其他与年龄相关的危险代谢状况发生的主要致病因素。我们最近发现 mTORC1 介导的途径控制脂肪细胞中的脂肪分解，并且我们建议确定我们观察到的分子机制和生理意义。