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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。硬脂酰辅酶A去饱和酶-1(SCD1)是一种脂肪生成酶，催化合成单链不饱和脂肪酸，单链不饱和脂肪酸是三酰甘油中的主要脂肪酸。靶向干扰SCO 1(SCD1-/-)的小鼠可以减少肥胖，提高胰岛素敏感性，并降低肝脏三酰甘油水平。此外，在SCD1-/-小鼠中，编码脂肪酸氧化和脂肪合成酶的基因在肝脏中的表达分别上调和下调。肥胖者的骨骼肌具有胰岛素抵抗，脂肪酸(FA)氧化速率降低，脂肪含量增加，所有这些都与Scd1的上调相一致。通过在非肥胖者的原代人类心肌细胞中过表达SCD1，通过增加IMTG积累和抑制线粒体b-氧化，导致脂肪酸分配改变，来检验这些发现的功能意义。这一建议的总体假设是，肥胖者骨骼肌中SCD1的上调导致脂肪堆积和胰岛素抵抗。这一假设将使用人体体内、体外和细胞培养研究模型进行验证。这项建议的目的是：1)检测骨骼肌FA代谢、骨骼肌SCDL活性和体内整体胰岛素敏感性指标之间的关系；2)在非肥胖和肥胖人的原代培养人心肌细胞中分别过度表达和下调SCDL基因转录，并检测底物代谢(FA和葡萄糖)和胰岛素信号转导；以及3)识别SCDL活性升高导致肌内脂肪堆积的机制(S)。总体而言，拟议的研究将提供有关SCDL在人类骨骼肌脂类堆积和胰岛素抵抗中的作用的生理学相关信息。了解肌肉内脂肪堆积的机制(S)对于开发可以消除这种疾病的药物治疗是至关重要的。

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.