Effect of Exercise on DNA Methylation and Metabolism in Human Adipose Tissue and Skeletal Muscle

Abstract

in total glucose homeostasis as reduced insulin sensitivity in fat cells results in increased hydrolysis of triglycerides, which may further increase whole-body insulin resistance. Additionally, adipose tissue is an endocrine organ and its capacity to secrete adipokines changes in response to environmental stimuli, such as exercise. Future exercise intervention studies should aim to investigate a combination of tissues involved in human metabolism, including skeletal muscle, adipose tissue and blood. We recently described the genome-wide pattern of DNA methylation in human subcutaneous adipose tissue of 23 healthy men before and after a 6-month exercise intervention [4]. In total, 485,577 individual CpG sites were investigated, broadly covering all human genes and different genomic regions, and the results can be seen as reference for the human methylome in adipose tissue. These results were also related to mRNA expression and, for a third of the genes with changes in DNA methylation greater than 5%, we also detected altered mRNA levels. Interestingly, we found a total of 17,975 individual CpG sites in or near 7663 genes with altered levels of DNA methylation after the exercise intervention. The absolute difference in DNA methylation before versus after exercise ranges from 0.2 to 10.9%, corresponding with increased or decreased DNA methylation by 6–38%. More specifically, we detected 18 obesity and 21 Type 2 diabetes candidate genes; for example, TCF7L2 and KCNQ1, with one or more CpG sites altered in response to exercise. To further study the effect of DNA methylation on adipocyte metabolism, we silenced two genes that displayed both increased DNA methylation and decreased mRNA expression in adipose tissue in response to exercise. Silencing of Hdac4 and Ncor2, Exercise is a physiological stressor with the ability to regulate whole-body energy balance and glucose homeostasis. Regular exercise is important for maintaining physical fitness and has many beneficial effects on the immune system and mental health, as well as the potential to prevent or treat metabolic diseases including obesity, cardiovascular diseases and Type 2 diabetes. Epigenetics has been suggested as a link between the ever-changing environment and the genome, with the potential to alter gene expression [1]. The complex epigenetic mechanisms that modulate gene expression include DNA methylation and histone modifications. Epigenetics, therefore, has the potential to contribute to phenotypic variation; however, to what extent is currently hard to tell and is likely to differ between cell types and individuals. Hence, it is also likely that the effect of physical exercise on gene expression and physiological parameters could partly be mediated by epigenetic factors. Studies investigating the effect of exercise on DNA methylation in human tissues are starting to emerge. However, as the epigenome differs between cell types [2], the number of methylomes to analyze is numerous. Most studies so far have focused on epigenetic changes in human skeletal muscle in response to exercise, and both acute and long-term interventions. The rationale for these studies is to find a mechanism for the finding that exercise alters mRNA and protein levels of genes involved in mitochondrial function and fuel utilization in skeletal muscle [3]. Less attention has been paid to the role of exercise on epigenetic changes in adipose tissue, and surprisingly also on the transcriptomic changes likely to occur in adipose tissue in response to exercise. Although adipose tissue only accounts for a small proportion of glucose clearance, it is important