MON-707 Lifestyle Intervention Therapy Modulates Global and Gene Specific DNA Methylation In Severely Obese Hypogonadal Men

Abstract Disclosure: S. bathina: None. V. Fuenmayor Lopez: None. M. prado: None. S.B. Teo: None. V.S. Davila: None. R.P. Chen: None. Background: Previous clinical studies suggested the modulation of DNA methylation by lifestyle intervention (LSI) therapy by diet and exercise; however, little information is available on the effect of long-term supervised LSI in the subgroup of severely obese men with hypogonadism. Objective: The objective of this study is to evaluate the impact of long-term aerobic exercise and diet on 1) gene specific DNA methylation markers, 2) to measure Global methylation, 5-MC% (5-methylated cytosine %) and 3) on adipogenic markers by mRNA expression in PBMC in severely obese hypogonadal men undergoing LSI after 12 months. Method: Data from 116 severely obese (BMI ≥35 kg/m2) hypogonadal men participating in an ongoing clinical trial of WL from lifestyle intervention aged 35-65 years old (NCT03490513) were analyzed. Total DNA methylation and 5-MC% were analyzed using a global DNA methylation kit assay. DNA methylation enzymes (DNMT1, 3A, 3B and fat mass and obesity associated gene (FTO) and adipogenic markers (PPARγ, CEBPα) expression were examined from buffy coat by real-time quantitative PCR at BL and 12M. Results: The mean age of the participants was 51.4±7.6 years with mean BMI 41.8 ±5.4 kg/m2. At the end of 12 months, participants lost an average of 4.2±5.9% weight from baseline. LSI significantly reduced the mRNA expression of DNMT1 (BL: 3.29±1.1 Vs 12M: 0.78±0.16, p=0.038), DNMT3a (BL: 1.28±0.18 Vs 12M: 0.81±0.09, p=0.028) and DNMT3b (BL: 0.97±0.15 Vs 12M: 0.64±0.07, p=0.05) and FTO (BL: 1.47±0.27 Vs 12M: 0.86±0.09, p=0.028). LSI also decreased mRNA levels of adipogenic markers, PPARγ (BL: 1.53±0.37 Vs 12M: 0.83±0.18, p=0.08), and CEBPα (BL: 1.59±0.32 Vs 12M: 0.76±0.18, p=0.045). To confirm these epigenetic changes are at DNA level, we analyzed 64 samples at 3 timepoints, ie, BL, 6 months (6M) and 12M. We found LSI significantly reduced the 5MC % (BL: 0.16 ± 0.01 Vs 6M: 0.107 ± 0.005, p=0.0014) and (BL: 0.16 ± 0.01 Vs 12M: 0.11± 0.007, p=0.0013) and global DNA methylation (BL: 0.54 ± 0.03 Vs 6M: 0.51 ± 0.02, p=0.41) and BL: 0.54 ± 0.03 Vs 12M: ± 0.45± 0.01, p=0.045) in DNA samples. Conclusions: Our results suggest that LSI decreases global methylation by modulation of DNMTs and FTO enzymes in our subjects of severely obese hypogonadal men. This is accompanied by reduced expression of adipogenic markers. Changes in methylation may contribute to overall changes in metabolic profile in the general population of subjects undergoing LSI. Presentation: Monday, July 14, 2025