Contribution of ATGL in skeletal muscle to lipid metabolism and insulin action

骨骼肌中 ATGL 对脂质代谢和胰岛素作用的贡献

基本信息

批准号：
7649793
负责人：
ERIN E. KERSHAW
金额：
$ 6.1万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649793
关键词：
1,2-diacylglycerol Abbreviations Acute Acyl Coenzyme A Adipose tissue Affect Canis familiaris Cells Ceramides Coenzyme A Complementary DNA Condition Deoxyglucose Deposition Diabetes Mellitus Diglycerides Disease Enzymes Esterification Euglycemic Clamping Fasting Fatty Acids Fatty acid glycerol esters Functional disorder Gene Expression Glucose Clamp Glycerides Homeostasis Hydrolysis In Vitro Insulin Insulin Resistance Israel Lead Link Lipase Lipids MM form creatine kinase Mediating Medical center Metabolic Metabolic Diseases Metabolic syndrome Monoglycerides Mus Muscle Muscle Fibers Nature Obesity Phenotype Play Polymerase Chain Reaction Protein Overexpression Public Health Rate Retroviridae Role Serum Skeletal Muscle Skeletal system Testing Time Tissues Training Transgenic Mice Triglycerides blood glucose regulation fatty acid metabolism gain of function glucose disposal glucose metabolism glucose uptake in vivo insight insulin sensitivity insulin signaling lipid metabolism novel obesity treatment oxidation promoter sterol esterase uptake

项目摘要

DESCRIPTION (provided by applicant): Obesity and the metabolic syndrome are global public health problems. These disorders are associated with ectopic deposition of triglycerides (TGs) and other lipid metabolites in non-adipose tissues such as skeletal muscle. Intramyocellular triglyceride (IMTG) accumulation is strongly associated with insulin resistance. The mechanisms underlying IMTG accumulation and its relationship to insulin resistance remain unclear. (ATGL) is a novel adipose-enriched lipase that mediates the initial rate-limiting step in TG hydrolysis. ATGL is also expressed in skeletal muscle, but its role in IMTG hydrolysis has not yet been explored. The central aim of this proposal is to evaluate the role of ATGL in skeletal IMTG hydrolysis and to evaluate the contribution of ATGL- mediated IMTG hydrolysis to lipid and glucose homeostasis. In this proposal, the metabolic consequences of ATGL gain-of-function in skeletal muscle will be evaluated 1) in vitro by generating skeletal muscle-derived C2C12 cells that are stably transfected with retrovirus containing murine ATGL cDNA (C2C12ATGL cells), and 2) in vivo by generating transgenic mice that express murine ATGL cDNA under the control of the skeletal muscle-specific murine muscle creatine kinase promoter (MCK-ATGL mice). Aim 1 will evaluate the effects ATGL overexpression in skeletal muscle on intramyocellular and systemic lipid metabolism. Aim 2 will evaluate the effects ATGL overexpression in skeletal muscle on intramyocellular and systemic glucose metabolism and insulin action. Evaluating the role of ATGL- mediated IMTG hydrolysis will promote the understanding of IMTGs in lipid metabolism and glucose metabolism/insulin action, thereby providing important insights into the pathophysiology and treatment of obesity, insulin resistance, and related metabolic disorders. Obesity and the metabolic syndrome are associated with deposition of excess fat (i.e. triglycerides) in multiple tissues. Fat deposition in skeletal muscle is associated with insulin resistance with can lead to diabetes. Adipose triglyceride lipase (ATGL) has recently been identified as a new enzyme that breaks down fat, but its role in skeletal muscle is not known. Evaluating the role of ATGL-mediated fat breakdown in skeletal muscle will provide important insights into the pathophysiology and treatment of obesity, insulin resistance, and related metabolic disorders.

描述（由申请人提供）：肥胖和代谢综合征是全球公共卫生问题。这些疾病与甘油三酯 (TG) 和其他脂质代谢物在非脂肪组织（如骨骼肌）中的异位沉积有关。肌细胞内甘油三酯（IMTG）积累与胰岛素抵抗密切相关。 IMTG 积累的机制及其与胰岛素抵抗的关系仍不清楚。 (ATGL) 是一种新型富含脂肪的脂肪酶，可介导 TG 水解的初始限速步骤。 ATGL 也在骨骼肌中表达，但其在 IMTG 水解中的作用尚未被探索。该提案的中心目的是评估 ATGL 在骨骼 IMTG 水解中的作用，并评估 ATGL 介导的 IMTG 水解对脂质和葡萄糖稳态的贡献。在本提案中，将评估骨骼肌中 ATGL 功能获得的代谢后果：1) 在体外，通过生成用含有鼠 ATGL cDNA 的逆转录病毒稳定转染的骨骼肌来源的 C2C12 细胞（C2C12ATGL 细胞）进行体外评估，以及 2)通过在骨骼肌特异性鼠肌肌酸激酶启动子（MCK-ATGL）的控制下产生表达鼠 ATGL cDNA 的转基因小鼠，在体内老鼠）。目标 1 将评估骨骼肌中 ATGL 过度表达对肌细胞内和全身脂质代谢的影响。目标 2 将评估骨骼肌中 ATGL 过度表达对肌细胞内和全身葡萄糖代谢以及胰岛素作用的影响。评估 ATGL 介导的 IMTG 水解的作用将促进对 IMTG 在脂质代谢和葡萄糖代谢/胰岛素作用中的理解，从而为肥胖、胰岛素抵抗和相关代谢紊乱的病理生理学和治疗提供重要见解。肥胖和代谢综合征与多个组织中过量脂肪（即甘油三酯）的沉积有关。骨骼肌中的脂肪沉积与胰岛素抵抗有关，可导致糖尿病。脂肪甘油三酯脂肪酶（ATGL）最近被确定为一种分解脂肪的新酶，但其在骨骼肌中的作用尚不清楚。评估 ATGL 介导的脂肪分解在骨骼肌中的作用将为肥胖、胰岛素抵抗和相关代谢紊乱的病理生理学和治疗提供重要的见解。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cold-Induced Thermogenesis Depends on ATGL-Mediated Lipolysis in Cardiac Muscle, but Not Brown Adipose Tissue.

DOI：
10.1016/j.cmet.2017.09.004
发表时间：
2017-11-07
期刊：
Cell metabolism
影响因子：
29
作者：
Schreiber R;Diwoky C;Schoiswohl G;Feiler U;Wongsiriroj N;Abdellatif M;Kolb D;Hoeks J;Kershaw EE;Sedej S;Schrauwen P;Haemmerle G;Zechner R
通讯作者：
Zechner R