Lifestyle Intervention Therapy Modulates Global DNA Methylation and Adipogenic Gene Expression in Severely Obese...

Background/Objectives: Previous studies have suggested that lifestyle intervention (LSI) therapies involving diet and exercise can modulate DNA methylation; however, whether this occurs in severely obese hypogonadal men undergoing weight loss from diet and exercise remains unclear. Methods: In this study, we investigated the effects of weight loss from diet and exercise on global DNA methylation as well as on the mRNA expression of specific demethylation enzymes, DNMT1, DNMT3A, and DNMT3B-in peripheral blood mononuclear cells (PBMCs) and DNA methylation markers in DNA of severely obese hypogonadal men. This is a secondary analysis of samples of severely obese (body mass index of ≥35 kg/m²) hypogonadal men undergoing weight loss from diet and exercise in addition to an aromatase inhibitor (anastrozole) or placebo for a total of 12 months. Results: LSI therapy significantly reduced global DNA methylation and 5-methylcytosine (5-mC) levels, decreased DNMT1, DNMT3A, and DNMT3B (p < 0.05) mRNA levels and markedly decreased CEBPα, FTO, and PPARγ mRNA expression. The reduction in global methylation was independent of aromatase inhibitor use. Conclusions: In summary, our findings suggest that LSI induces epigenetic modifications in leukocytes, possibly through the regulation of DNMT gene expression. Future studies are warranted to clarify the mechanistic pathways linking lifestyle-induced epigenetic alterations to metabolic health outcomes.