The present study revealed that, despite the anthropometric and body composition changes, bariatric surgery was able to increase the methylation levels of specific CpG site on the GHRL gene. These results show how the bariatric surgery modulates the methylation levels of the appetite genes, trying to reduce the appetite signal. Since the GHRL is an orexigenic gene, we expected this increase in methylation levels after surgery; however, hypermethylation of the GHRL gene after gastric bypass does not corroborate with the literature. In a study conducted with 35 patients undergoing vertical gastrectomy surgery, the authors found that four CpGs in the promoter region of the GHRL gene did not change after six months of the procedure [22]. In fact, another study revealed a wide individual variability in the methylation level of the GHRL gene after one year of RYGB; however, with no significant difference [23]. On the other hand, some authors demonstrated that plasma ghrelin increases after gastric bypass surgery in patients who active weight loss [24].
In addition, it should be noted a positive correlation between changes in methylation level of specific CpG sites in AGRP and GHRL genes with fat mass loss, in which higher increases in methylation levels after surgery correlated with bigger loss of fat mass after bariatric procedure. These results suggest that methylation level of genes related to appetite and satiety control have an effect on surgery outcomes. Considering that methylation process of gene promoter regions implies in gene silence [25], we hypothesize that greater methylation level led to lower gene expression with consequent lower appetite signal and then greater body fat reduction as bariatric surgery results. Further studies using downstream strategies such as gene expression and protein expression, may elucidate the role of these specific CpG methylation in the general context. In line of this, study conducted with obese women after low caloric diet intervention evidenced that those patients with lower serum ghrelin levels at baseline seem to be more resistant to fat mass loss [26]. In contrast, Crujeiras et. al. [27] after evaluated obese/overweight patients followed an 8-week hypocaloric diet evidenced that those patients with lower ghrelin levels at baseline were more inclined to regain the weight lost during the intervention.
The potential contribution of epigenetic modifications of appetite/satiety genes on bariatric surgery outcome has not yet been fully described. As above mentioned, some evidences are concerning serum protein levels and results about DNA methylation are scarce. A recent review study showed the importance of having more interventional studies between DNA methylation and obesity, since most studies are of association, correlating DNA methylation with phenotypic results [28]. Studies are needed to elucidate the molecular mechanisms in which DNA methylation and obesity are linked. Thus, the understanding of the transcriptional regulation of genes that participate in the appetite/satiety pathway is crucial to understand the pathophysiology of the disease, since changes in the DNA methylation pattern of genes can contribute to modify expression and modulate functions in important pathways metabolic, as well as, to establish biomarkers for predicting obesity-treatment outcomes.
This study presented some limitations such as the use of blood sample, however, nerve tissues are not viable. Another important limitation refers to the sample size, when presented in a small number, allows to consider the results found only for the population in question.