Metabolic and molecular basis of the complex interaction between protein metabolism and insulin action in human skeletal muscle

在膳食脂肪可用性增加的条件下，骨骼肌葡萄糖代谢充分响应胰岛素信号传导的能力受损（称为“胰岛素抵抗”，IR），这被认为是骨骼肌内脂质细胞内蓄积的结果。IR是代谢和心血管疾病发展的危险因素，因此是代谢健康的重要调节剂。由于胰岛素信号传导也是骨骼肌氨基酸递送和代谢的组成部分，因此脂质诱导的IR也可能损害骨骼肌响应膳食氨基酸充分合成新蛋白质的能力（称为“合成代谢抵抗”，AR）。事实上，我们最近已经表明，人体脂质利用率的升高可以诱导骨骼肌IR和AR对氨基酸摄入的反应。然而，目前还不知道哪些脂肪酸是致病的，或潜在的细胞机制。该项目的目的是阐明将源自不同类型膳食脂肪酸的细胞内脂质种类的积累与人骨骼肌中IR和AR的发展相结合的机制。拟议的工作将采用一种综合的方法，将结合联合收割机人类为基础的调查与骨骼肌细胞为基础的实验。基于人体的研究的目的是研究通过饮食干预对骨骼肌IR和AR的影响，在瘦和超重的健康人中操纵循环脂质。来自人骨骼肌的原代细胞培养物将用于阐明从人体实验中确定为关键靶标的蛋白质的功能重要性，以建立不同脂质物质影响IR和AR的特定途径。

The ability of skeletal muscle glucose metabolism to respond adequately to insulin signalling is compromised (termed 'insulin resistance', IR) under conditions of increased dietary fat availability and this is thought to be a consequence of the intracellular accumulation of lipid within skeletal muscle. IR is a risk factor for the development of metabolic and cardiovascular disease and therefore an important modulator of metabolic health. As insulin signalling is also integral to skeletal muscle amino acid delivery and metabolism, it is likely that lipid-induced IR may also compromise the ability of skeletal muscle to adequately synthesise new protein in response to dietary amino acids (termed 'anabolic resistance', AR). Indeed, we have recently shown that elevating lipid availability in humans can induce skeletal muscle IR and AR in response to amino acid ingestion. However, it is not known which fatty acids are causative, or the underlying cellular mechanisms. The aim of this project is to elucidate the mechanisms that couple the accumulation of intracellular lipid species originating from different types of dietary fatty acids to the development of both IR and AR in human skeletal muscle. The proposed work will employ an integrated approach that will combine human based investigations with skeletal muscle cell based experiments. The objectives of the human based studies are to investigate the impact of manipulating circulating lipids in both lean and overweight healthy humans via dietary interventions on both skeletal muscle IR and AR. Primary cell cultures from human skeletal muscle will be used to elucidate the functional importance of proteins identified as key targets from the human experiments to establish the specific pathways by which different lipid species affect both IR and AR.