Regulation of lipolysis by mTORC1

mTORC1 对脂肪分解的调节

• 批准号: 8328642
• 负责人: Konstantin V Kandror
• 金额: $ 24.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328642
• 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

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.

描述（由申请人提供）：脂解和循环游离脂肪酸的失调水平不足，代表了胰岛素抵抗，2型糖尿病，心血管疾病和其他有害代谢状况的重要原因因素，这些因素迅速迅速前进，并在老年人中特别严重。限制人口老龄化的代谢疾病将改善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的激活抑制了限制速率脂肪酶的表达，ATGL抑制了基础和cAMP刺激的脂解，并引起甘油三酸酯在脂肪和穆斯科细胞中的明显积累。 MTORC1的抑制具有相反的效果。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。该屏幕的结果表明，MTORC1通过早期生长反应（EGR）家族的转录因子抑制ATGL表达。因此，在特定目标1中，我们建议从机械学上确定EgR1/2在MTORC1介导的ATGL和脂肪分解中的作用，而在特定目标2中，我们将研究MTORC1/EGR1/2轴在代谢性疾病和衰老中的作用。我们认为，我们的工作将有助于建立MTORC1介导的途径作为FFA稳态的中心控制者和该途径的失调 - 作为代谢疾病的主要病因学因素，该病因限制了美国人群的HealthSpan和寿命。