Human skeletal muscle lipid metabolism

Obesity and ageing are major risk factors for the development of chronic conditions such as cardiovascular disease, Type 2 diabetes, and musculoskeletal disorders. Ectopic accumulation of lipid metabolites is a major feature of obese human skeletal muscle and a normal process of ageing. Moreover this lipid accumulation has a major metabolic impact since various fatty acid metabolites such as acyl-CoAs, acylcarnitines, diacylglycerols and ceramides have been shown to impair insulin action. Such lipid accumulation is likely due to a combination of excess energy intake and physical inactivity. However, which specific lipid metabolism pathways are affected in obese/older individuals has not been delineated in humans in vivo, nor has the specific lipid metabolites causing defects in insulin or anabolic/catabolic signalling. In fact we still know very little about how fatty acids are partitioned in to these lipid pools in humans. This would clearly yield vital information for development of interventions. We have recently obtained grant funding to utilise stable isotope fatty acid tracers ([13C16]palmitate and [2H31]palmitate) to study in vivo lipid metabolism in older individuals and individuals with type 2 diabetes. In particular, the oral [2H31]palmitate ingestion method is highly unique in representing minimally invasive approaches to studying lipid turnover, metabolism, and oxidation in volunteers under their free-living conditions of normal daily activities. Moreover, as the tracers are incorporated into a number of dynamically active lipid pools these indices can be assessed temporally over hours to days in muscle samples obtained from human participants using our MRC/Arthritis Research Centre for Musculoskeletal Ageing Research mass-spectrometry facillities. Thus, the aim of the present the studentship will be to utilise the above novel tracer methodology for the detection of an array of muscle lipid metabolites, and the incorporation of the afore mentioned tracers into the lipidomic pool of skeletal muscle samples obtained from human participants before and after interventions aimed to manipulate fat metabolism. Despite being a powerful tool in our understanding of skeletal muscle metabolism, application of stable isotopes to lipid biomarker identification is an exceptionally novel approach and remains underexplored in the area of human metabolic physiology research. For example, there have been several recent high impact metabolomic studies identifying increased plasma lipid metabolites as strong predictors of the onset of Type 2 diabetes in obesity, but the strength of this project is the added dimension of studying lipid metabolite flux measured within the actual tissue where lipid metabolites originate under free-living conditions. The specific objectives are: 1). Measure the turnover and content of lipid metabolites in skeletal muscle samples obtained from studies where lipid availability and insulin sensitivity has been manipulated acutely (physical activity), chronically (weight loss), nutritionally (L-carnitine), and pharmacologically (Acipimox) in humans. 2). Validate key metabolites in cells studies and/or skeletal muscle samples obtained from insulin resistance individuals e.g. type 2 diabetes. These approaches clearly fit the BBSRC theme of Molecules, Cells and Organisms (MCO) and specific aim of understanding the mechanisms by which diet and physical activity influence health across the life course.