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

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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.