STEAROYL-COA DESATURASE-1 IN SKELET AL MUSCLE LIPID ACCUMULATN & INSULIN RESIST

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Stearoyl-CoA desaturase-1 (SCD1) is a lipogenic enzyme that catalyzes the synthesis of monounsaturated fatty acids, which are the predominate fatty acids of triacylglycerols. Mice with a targeted disruption of SCO 1 (SCD1-/-) have reduced adiposity, increased insulin sensitivity, and reduced levels of hepatic triacylglycerols. Additionally, in SCD1-/- mice, hepatic expression of genes encoding enzymes of fatty acid oxidation and lipid synthesis is up regulated and down regulated, respectively. Skeletal muscle of obese humans is insulin resistant, possesses reduced rates of fatty acid (FA) oxidation, and elevated lipid content, all of which occurs in concert with an upregulation of SCD1. Functional implications of these findings were tested by overexpressing SCD1 in primary human myocytes from nonobese subjects, which resulted in altered fatty acid partitioning by increasing IMTG accumulation and inhibiting mitochondrial b-oxidation.The overall hypothesis of this proposal is that an upregulation of SCDl in skeletal muscle of obese humans causes lipid accumulation and insulin resistance. This hypothesis will be tested using human in vivo, in vitro, and cell culture research models. The objectives of this proposal are to: 1) examine relationships between in vitro measures of skeletal muscle FA metabolism, skeletal muscle SCDl activity, and in vivo measures of wholebody insulin sensitivity; 2) over express and knockdown SCDl gene transcription in primary human myocytes cultured from nonobese and obese humans, respectively, and examine substrate metabolism (FA and glucose) and insulin signaling; and 3) discern the mechanism(s) by which elevated SCDl actwity results in intramuscular lipid accumulation. Overall, the proposed studies will provide physiologically relevant information on the role of SCDl in skeletal muscle lipid accumulation and insulin resistance in humans. Understanding the mechanism(s) responsible for intramuscular lipid accumulation is essential for developing pharmacological treatments that could abolish this disorder.