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

在饮食脂肪供应增加的情况下，骨骼肌葡萄糖代谢对胰岛素信号做出充分反应的能力受到损害(称为胰岛素抵抗，IR)，这被认为是骨骼肌细胞内脂肪积聚的结果。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因子。由于胰岛素信号对骨骼肌氨基酸的传递和代谢也是不可或缺的，脂质诱导的IR很可能也会损害骨骼肌对饮食氨基酸的反应，充分合成新蛋白质的能力(称为合成代谢抵抗，AR)。事实上，我们最近已经证明，提高人类的脂肪利用率可以诱导骨骼肌对氨基酸摄取的IR和AR反应。然而，目前尚不清楚哪些脂肪酸是致病原因，也不知道其潜在的细胞机制。该项目的目的是阐明源于不同类型膳食脂肪酸的细胞内脂肪物种的积累与人类骨骼肌IR和AR的发展之间的耦合机制。这项拟议的工作将采用一种综合方法，将基于人类的研究与基于骨骼肌细胞的实验相结合。这项以人体为基础的研究的目的是调查通过饮食干预对骨骼肌IR和AR的影响，在瘦身和超重的健康人中操纵循环血脂的影响。来自人类骨骼肌的原代细胞培养将被用来阐明从人体实验中被确定为关键靶点的蛋白质的功能重要性，以建立不同脂质物种影响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.