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

<b>Background/Objectives:</b> 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. <b>Methods:</b> 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, <i>DNMT1</i>, <i>DNMT3A</i>, and <i>DNMT3B</i>-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. <b>Results:</b> LSI therapy significantly reduced global DNA methylation and 5-methylcytosine (5-mC) levels, decreased <i>DNMT1</i>, <i>DNMT3A</i>, and <i>DNMT3B</i> (<i>p</i> < 0.05) mRNA levels and markedly decreased <i>CEBPα</i>, <i>FTO</i>, and <i>PPARγ</i> mRNA expression. The reduction in global methylation was independent of aromatase inhibitor use. <b>Conclusions:</b> In summary, our findings suggest that LSI induces epigenetic modifications in leukocytes, possibly through the regulation of <i>DNMT</i> gene expression. Future studies are warranted to clarify the mechanistic pathways linking lifestyle-induced epigenetic alterations to metabolic health outcomes.