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[Abstract] DNA methylation could provide a link between environmental, genetic factors and weight control and can modify gene expression pattern. This study aimed to identify genes, which are differentially expressed and methylated depending on adiposity state by evaluating normal weight women and obese women before and after bariatric surgery (BS). We enrolled 24 normal weight (BMI: 22.5 ± 1.6 kg/m2) and 24 obese women (BMI: 43.3 ± 5.7 kg/m2) submitted to BS. Genome-wide methylation analysis was conducted using Infinium Human Methylation 450 BeadChip (threshold for significant CpG sites based on delta methylation level with a minimum value of 5%, a false discovery rate correction (FDR) of q < 0.05 was applied). Expression levels were measured using HumanHT-12v4 Expression BeadChip (cutoff of p ≤ 0.05 and fold change ≥2.0 was used to detect differentially expressed probes). The integrative analysis of both array data identified four genes (i.e. TPP2, PSMG6, ARL6IP1 and FAM49B) with higher methylation and lower expression level in pre-surgery women compared to normal weight women: and two genes (i.e. ZFP36L1 and USP32) that were differentially methylated after BS. These methylation changes were in promoter region and gene body. All genes are related to MAPK cascade, NIK/NF-kappaB signaling, cellular response to insulin stimulus, proteolysis and others. Integrating analysis of DNA methylation and gene expression evidenced that there is a set of genes relevant to obesity that changed after BS. A gene ontology analysis showed that these genes were enriched in biological functions related to adipogenesis, orexigenic, oxidative stress and insulin metabolism pathways. Also, our results suggest that although methylation plays a role in gene silencing, the majority of effects were not correlated.

[Abstract] Background/objectives: Obesity has been associated with gene methylation regulation. Recent studies have shown that epigenetic signature plays a role in metabolic homeostasis after Roux-en Y gastric bypass (RYGB). To conduct a genome-wide epigenetic analysis in peripheral blood to investigate whether epigenetic changes following RYGB stem from weight loss or the surgical procedure per se. Subjects/methods: By means of the Infinium Human Methylation 450 BeadChip array, global methylation was analyzed in blood of 24 severely obese women before and 6 months after RYGB and in 24 normal-weight women (controls). Results: In blood cells, nine DMCpG sites showed low methylation levels before surgery, methylation levels increased after RYGB and neared the levels measured in the controls. Additionally, 44 CpG sites associated with the Wnt and p53 signaling pathways were always differently methylated in the severely obese patients as compared to the controls and were not influenced by RYGB. Finally, 1638 CpG sites related to inflammation, angiogenesis, and apoptosis presented distinct methylation in the post-surgery patients as compared to the controls. Conclusion: Bariatric surgery per se acts on CpGs related to inflammation, angiogenesis, and endothelin-signaling. However, the gene cluster associated with obesity remains unchanged, suggesting that weight loss 6 months after RYGB surgery cannot promote this effect.