Physical activity (PA) is an important lifestyle intervention that can influence public health and help tackle the current global obesity challenge. The UK government has issued recommendations on regular PA levels, however individual responses to PA vary, and sedentary lifestyles present a significant risk to public health. Causes of obesity are complex and multi-faceted; genetic variations are a contributing factor, with specific genes such as the fat mass and obesity-associated (FTO) gene known to be strongly involved with obesity and related health conditions. Epigenetic studies examine the effect of PA as an external influence on the control of genes and associated molecular pathways, without affecting the DNA sequence itself. Methylation of DNA sequences in some gene promoter regions (CpG sites) have been found to be affected by PA, affecting gene transcription and expression. An increase in methylation levels (hypermethylation) restricts the action of the gene, whereas a decrease in methylation (hypomethylation) reduces control and regulation of the gene.  

This systematic review and meta-analysis aimed to identify specific CpG sites affected by various levels of PA in genes and pathways associated with obesity. The review was registered with PROSPERO and followed PRISMA guidelines. Databases searched included PubMed, SportDISCUS, Embase, Scopus, and Web of Science. Epigenomic DNA methylation analysis studies performed on adult participants with no underlying health conditions were included, using adipose, skeletal muscle or blood sample tissue types. Population studies or PA intervention studies were considered. Articles were screened and selection decisions recorded using Rayyan AI software. Stated CpG sites were extracted from study data and compiled, with gene locations confirmed using the Epigenome-Wide Association Studies (EWAS) catalogue. Six studies comprising of 770 participants were selected for inclusion in this meta-analysis. A total of 257 CpG sites were identified as significantly differentially methylated in physically active participants, and 134 of these CpG sites were located in 92 genes associated with obesity-related pathways. Genes identified as differentially regulated in multiple tissue types and studies are JAZF1 (insulin signalling, and lipid and carbohydrate metabolism pathways) and NAV1 (mTOR signalling pathway). Multiple differentially methylated genes belonged to pathways associated with the lipid metabolism or insulin signalling pathway. To conclude, the current epigenomic meta-analysis showed that PA levels induce differential DNA methylation changes on genes affecting metabolism. To further understand the positive molecular effects of PA, these candidate genes should be investigated further and compared between various levels of a physically active population.