Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure

雷帕霉素代谢和能量消耗途径的机制目标

基本信息

批准号：
9904610
负责人：
David A Guertin
金额：
$ 48.95万
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：
2013
资助国家：
美国
起止时间：
2013-07-05 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904610
关键词：
AKT1 gene AKT2 gene ATP Citrate (pro-S)-Lyase Acetates Acetyl Coenzyme A Acetylation Adipocytes Adipose tissue Biochemical Brown Fat Cardiovascular Diseases Cell Line Cell membrane Cells Chronic Disease Coenzyme A Ligases Complex Data Deacetylase Deacetylation Diet Disease Energy Metabolism Epidemic Epigenetic Process Equilibrium FOXO1A gene FRAP1 gene Family member Fatty Acids Fatty Liver Fatty acid glycerol esters Funding Gene Expression Genetic Models Genetic Programming Genetic Transcription Genetically Engineered Mouse Goals Grant Healthcare Systems High Fat Diet Histone Acetylation Homeostasis Impairment In Vitro Insulin Resistance Link Lipids Lipolysis Liver diseases Malignant Neoplasms Metabolic Metabolic Control Metabolic Diseases Metabolic Pathway Metabolism Modeling Molecular Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutritional Obesity Organism Overnutrition Overweight PDPK1 gene Pathway interactions Pharmacology Phenotype Phosphorylation Phosphotransferases Prevalence Production Proteomics Proto-Oncogene Proteins c-akt Publishing Regulation Research Risk Factors Role Second Messenger Systems Signal Pathway Signal Transduction Signal Transduction Pathway Testing Therapeutic Thermogenesis Tissues Triglycerides United States Work adipocyte differentiation base detection of nutrient diabetogenic energy balance fatty acid oxidation feeding flexibility in vivo insulin sensitivity interdisciplinary approach knowledge base lipid biosynthesis lipid metabolism metabolomics novel phosphoproteomics prevent programs recruit thermal stress transcription factor

项目摘要

The long-term goal of this proposal is to elucidate mechanisms that regulate energy balance. Here, we investigate the regulation of lipid handling and energy homeostasis in adipose tissue with a specific focus on elucidating how signal transduction pathways intersect with metabolic pathways to control thermogenesis and insulin sensitivity. Healthy adipocytes dynamically switch between anabolic and catabolic lipid metabolism upon fluctuations in systemic nutrient availability and thermal stress to support the organism's energetic demands. Maintaining this metabolic flexibility depends upon signals that tightly coordinate de novo fatty acid and triacylglycerol synthesis with lipolysis and fatty acid oxidation. For unclear reasons, overweight or obesity impairs this metabolic flexibility and leads to chronic diseases such as insulin resistance, T2DM, fatty liver disease, cardiovascular disease, and certain cancers. The long-term goal of this research is to understand the molecular basis of how adipocytes sense and respond to nutrients to control energy balance, and how over-nutrition reprograms these signaling circuits to cause disease. The specific objective of this proposal is to elucidate the mechanisms by which the mechanistic target of rapamycin complex 2 (mTORC2), which we previously showed is a key regulator of adipocyte lipid metabolism, links systemic nutrient availability with intracellular metabolic control. To test this, we are taking a multidisciplinary approach utilizing genetically engineered mice, primary cell lines, and pharmacological agents in combination with state-of-the-art proteomics and metabolite profiling to delineate the downstream metabolic circuits under direct and indirect mTORC2 control that are relevant to adipose tissue related diseases. Our previous work on this project revealed that inhibiting mTORC2 in brown adipocytes enhances diet-induced thermogenesis, that inhibiting mTORC2 in white adipose tissue causes severe insulin resistance, that ChREBP is a novel mTORC2 effector that regulates de novo lipogenesis downstream of mTORC2, and that the consequences of mTORC2 loss in brown and white fat are phenotypically similar to the effects of a diabetogenic high fat diet on these tissues. Building upon this knowledge base, we will continue elucidating the mechanisms by which mTORC2 programs adipocyte metabolism in Aim 1, investigate the mechanistic similarities and potential connection between mTORC2 loss and high fat diet on adipocyte metabolism in Aim 2, and investigate a novel transcriptional circuit under direct mTORC2 control that regulates adipocyte lipid metabolism in Aim 3. Elucidating how nutrient-sensing signaling pathways like the mTOR pathway link nutritional signals to metabolic regulation in adipocytes has important implications for advancing therapies to treat obesity, type 2 diabetes, and related metabolic diseases.

该提案的长期目标是阐明调节能量平衡的机制。在这里，我们研究脂肪组织中脂质处理和能量稳态的调节，特别关注阐明信号转导途径如何与代谢途径交叉以控制产热和胰岛素敏感性。健康的脂肪细胞根据全身营养可用性和热应激的波动在合成代谢和分解代谢脂质代谢之间动态切换，以支持生物体的能量需求。维持这种代谢灵活性取决于紧密协调从头脂肪酸和三酰甘油合成与脂肪分解和脂肪酸氧化的信号。由于不明原因，超重或肥胖会损害这种代谢灵活性，并导致胰岛素抵抗、T2DM、脂肪肝、心血管疾病和某些癌症等慢性疾病。这项研究的长期目标是了解脂肪细胞如何感知和响应营养物质以控制能量平衡的分子基础，以及营养过剩如何重新编程这些信号回路以导致疾病。该提案的具体目标是阐明雷帕霉素复合物 2 (mTORC2) 的机制靶标（我们之前表明它是脂肪细胞脂质代谢的关键调节因子）将全身营养可用性与细胞内代谢控制联系起来的机制。为了测试这一点，我们正在采取多学科方法，利用基因工程小鼠、原代细胞系和药物制剂，结合最先进的蛋白质组学和代谢物分析来描绘直接和间接 mTORC2 控制下的下游代谢回路。与脂肪组织相关疾病有关。我们之前在该项目上的工作表明，抑制棕色脂肪细胞中的 mTORC2 会增强饮食诱导的生热作用，抑制白色脂肪组织中的 mTORC2 会导致严重的胰岛素抵抗，ChREBP 是一种新型 mTORC2 效应子，可调节 mTORC2 下游的从头脂肪生成，并且棕色和白色脂肪中 mTORC2 缺失的后果在表型上与致糖尿病的高脂肪饮食对这些组织的影响相似。在此知识基础上，我们将继续在目标 1 中阐明 mTORC2 编程脂肪细胞代谢的机制，在目标 2 中研究 mTORC2 缺失和高脂肪饮食对脂肪细胞代谢的机制相似性和潜在联系，并在目标 2 中研究新的转录回路。目标 3 中调节脂肪细胞脂质代谢的直接 mTORC2 控制。阐明 mTOR 通路等营养感应信号通路如何将营养信号与代谢调节联系起来脂肪细胞对于推进治疗肥胖、2 型糖尿病和相关代谢疾病的疗法具有重要意义。