An integrative profiling of metabolome and transcriptome in the plasma and skeletal muscle following an exercise intervention in diet-induced obese mice

Abstract Exercise intervention at the early stage of type 2 diabetes mellitus (T2DM) can aid in the maintenance of blood glucose homeostasis and prevent the development of macrovascular and microvascular complications. However, the exercise-regulated pathways that prevent the development of T2DM remain largely unclear. In this study, two forms of exercise intervention, treadmill training and voluntary wheel running, were conducted for high-fat diet (HFD)-induced obese mice. We observed that both forms of exercise intervention alleviated HFD-induced insulin resistance and glucose intolerance. Skeletal muscle is recognized as the primary site for postprandial glucose uptake and for responsive alteration beyond exercise training. Metabolomic profiling of the plasma and skeletal muscle in chow, HFD, and HFD-exercise groups revealed robust alterations in metabolic pathways by exercise intervention in both cases. Overlapping analysis identified 9 metabolites, including beta-alanine, leucine, valine, and tryptophan, which were reversed by exercise treatment in both the plasma and skeletal muscle. Transcriptomic analysis of gene expression profiles in the skeletal muscle revealed several key pathways involved in the beneficial effects of exercise on metabolic homeostasis. In addition, integrative transcriptomic and metabolomic analyses uncovered strong correlations between the concentrations of bioactive metabolites and the expression levels of genes involved in energy metabolism, insulin sensitivity, and immune response in the skeletal muscle. This work established two models of exercise intervention in obese mice and provided mechanistic insights into the beneficial effects of exercise intervention on systemic energy homeostasis.