Alterations of sorbin and SH3 domain containing 3 (SORBS3) in human skeletal muscle following Roux-en-Y gastric bypass surgery.

Background: Obesity is a disease that is caused by genetic and environmental factors. However, epigenetic mechanisms of obesity are less well known. DNA methylation provides a mechanism whereby environmental factors can influence gene transcription. The aim of our study was to investigate skeletal muscle DNA methylation of sorbin and SH3 domain containing 3 () with weight loss induced by Roux-en-Y gastric bypass (RYGB).

Results: Previously, we had shown increased methylation (5.0 to 24.4%) and decreased gene expression (fold change - 1.9) of with obesity (BMI > 30 kg/m) compared to lean controls. In the present study, basal muscle biopsies were obtained from seven morbidly obese (BMI > 40 kg/m) female subjects pre- and 3 months post-RYGB surgery, in combination with euglycemic-hyperinsulinemic clamps to assess insulin sensitivity. We identified 30 significantly altered promoter and untranslated region methylation sites in using reduced representation bisulfite sequencing (RRBS). Twenty-nine of these sites were decreased (- 5.6 to - 24.2%) post-RYGB compared to pre-RYGB. We confirmed the methylation in 2 (Chr.8:22,423,690 and Chr.8:22,423,702) of the 29 decreased sites using pyrosequencing. This decreased methylation was associated with an increase in gene expression (fold change + 1.7) post-surgery. In addition, we demonstrated that promoter methylation in vitro significantly alters reporter gene expression ( < 0.0001). Two of the methylation sites (Chr.8:22,423,111 and Chr.8:22,423,205) were strongly correlated with fasting plasma glucose levels ( = 0.9,  = 0.00009 and  = 0.8,  = 0.0010). Changes in gene expression post-surgery were correlated with obesity measures and fasting insulin levels ( = 0.5 to 0.8;  < 0.05).

Conclusions: These results demonstrate that methylation and gene expression are altered in obesity and restored to normal levels through weight loss induced by RYGB surgery.