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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。硬脂酰辅酶A去饱和酶-1（SCD 1）是一种脂肪生成酶，催化单不饱和脂肪酸的合成，单不饱和脂肪酸是三酰甘油的主要脂肪酸。具有SCO 1（SCD 1-/-）的靶向破坏的小鼠具有减少的肥胖、增加的胰岛素敏感性和降低的肝三酰甘油水平。此外，在SCD 1-/-小鼠中，编码脂肪酸氧化和脂质合成酶的基因的肝脏表达分别上调和下调。肥胖人的骨骼肌是胰岛素抵抗的，具有降低的脂肪酸（FA）氧化速率和升高的脂质含量，所有这些都与SCD 1的上调一致发生。通过在来自非肥胖受试者的原代人肌细胞中过表达SCD 1来测试这些发现的功能意义，这通过增加IMTG积累和抑制线粒体β-oxidation.The总体假设的建议是，在肥胖人的骨骼肌中上调SCD 1导致脂质积累和胰岛素抵抗。该假设将使用人体体内、体外和细胞培养研究模型进行检验。本发明的目的是：1）检查骨骼肌FA代谢的体外测量、骨骼肌SCD 1活性和全身胰岛素敏感性的体内测量之间的关系; 2）分别在从非肥胖和肥胖人培养的原代人肌细胞中过表达和敲低SCD 1基因转录，并检查底物代谢。（FA和葡萄糖）和胰岛素信号传导;和3）辨别升高的SCD 1活性导致肌内脂质积累的机制。总体而言，所提出的研究将提供关于SCD 1在人类骨骼肌脂质积累和胰岛素抗性中的作用的生理学相关信息。了解肌内脂质蓄积的机制对于开发可以消除这种疾病的药物治疗至关重要。

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.