GENOME-WIDE METHYLATION APPROACH IDENTIFIES GENES INVOLVED IN AMPK SIGNALING AND INSULIN RESISTANCE PATHWAYS IN OBESE WOMEN SUBjecTED TO GASTRIC BYPASS

Abstract

Introduction: The approach of nutritional genomics allows analyses of the associations between the genome and food. Epigenetic patterns related to obesity may explain the risk of developing this disease and associated comorbidities. Knowledge of the DNA methylation pattern before and after interventions for weight loss may promote understanding of the molecular mechanisms that determine the treatment`s efficacy. Aim: We aimed to evaluate the whole blood DNA methylation changes 6-months after Roux-en-Y gastric bypass (RYGB) in a genome-wide methylation approach. Materials and Methods: The genome-wide methylation pattern was measured in DNA samples isolated from circulating leukocytes and were hybridized in the Infinium HumanMethylation 450k BeadChip. Data were compared between samples from obese women (body mass index (BMI) 44.2±6.6 kg/m² and age of 36.4±10.7 years) (n= 12) before and 6 months after RYGB. The methylation level of each cytosine was expressed as a β-value (fluorescence intensity ratio of the methylated and the unmethylated alleles) that ranged between 0 (unmethylated) and 1 (completely methylated). Data normalization, statistical filtering, and raw data were transformed into β-values using the Genome Studio Illumina software (V2010.3). Results: After adjustments, we found 473.999 final valid CpGs sites. Differentially methylation analysis identified 1,142 differentially methylated CpG sites (DMCpGs) after RYGB. Thereby, a hypermethylated profile was observed after RYGB with 977 CpGs sites. On the other hand, 165 CpGs sites became hypomethylated after surgery. Specifically, the methylation levels of AKT, PPARG, ADIPOR2, SREBF1, PTEN, IL-12B, genes involved in AMPK signaling and insulin resistance pathways exhibited statistically significant hypermethylation between periods (q <0.05; p <0.001). Conclusion: With a genome-wide methylation approach, we showed that RYGB promotes methylation changes of blood DNA, mainly hypermethylation in genes involved in AMPK signaling and insulin resistance pathways. Therefore, this study provided new and valuable DNA methylation biomarkers of obesity through peripheral blood analysis, which is essential for personalized weight loss strategies Acknowledgements : SA£o Paulo Research Foundation (FAPESP) grant #2015/18669-0