Acyl-CoA Synthetase: Structure, Function and Regulation

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DESCRIPTION (provided by applicant): In response to NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications, we propose a Competitive Revision to the Parent Grant DK 59935: Acyl-CoA synthetases: Structure, function, regulation. Increased use of acyl-CoAs in downstream metabolic pathways such as TAG synthesis, storage, and lipoprotein secretion and decreased acyl-CoA use in FA oxidation pathways are widely believed to underlie the development of nutritional disorders such as obesity, fatty liver, atherosclerosis and diabetes. The Parent Grant proposed to use gain-of function and loss-of function studies to analyze the roles of the major ACSL isoforms in adipose tissue, liver and heart. We found that loss of ACSL1 in heart and adipose tissue results in a profound impairment in the use of fatty acids for ¿-oxidation. With this Competitive Revision, we now propose to extend our studies to skeletal muscle, a major tissue responsive to insulin action. Using Acsl1Flox/Flox mice crossed with myogenin-Cre mice, we will create mice deficient in ACSL1 solely in skeletal muscle (Acsl1MusKO mice) and study their responsiveness to diet-induced obesity and insulin resistance and their ability to exercise. We predict that Acsl1MusKO mice will be highly insulin-sensitive, and that exercise will not improve insulin sensitivity. Further, the high fat diet will induce obesity but not insulin resistance, although the liver may become insulin resistant if the high fat diet induces hepatic steatosis. We also predict that these mice will have severely impaired ability to exercise. These studies will allow us to separate the effects of muscle lipid storage from the insulin resistance believed to be induced by impaired FA oxidation and will clarify the role of ACSL1 in directing FA towards ¿-oxidation. This revision expands the scope of the specific aims of the Parent Grant by allowing us to explore novel ideas related to the role of fat metabolism and insulin resistance. In addition, the revision will both accelerate the tempo of scientific research on muscle's role in insulin resistance, and it will allow for job creation. Specifically, it will allow us to hire an additional postdoctoral fellow and an additional graduate student. PUBLIC HEALTH RELEVANCE: This revision expands the scope of the specific aims of the Parent Grant by allowing us to explore novel ideas related to the role of fat metabolism and insulin resistance. In addition, the revision will both accelerate the tempo of scientific research on muscle's role in insulin resistance, and it will allow for job creation. Specifically, it will allow us to hire an additional postdoctoral fellow and an additional graduate student.