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

Abstract

BackgroundObesity 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 (SORBS3) with weight loss induced by Roux-en-Y gastric bypass (RYGB).ResultsPreviously, we had shown increased methylation (5.0 to 24.4%) and decreased gene expression (fold change − 1.9) of SORBS3 with obesity (BMI > 30 kg/m2) compared to lean controls. In the present study, basal muscle biopsies were obtained from seven morbidly obese (BMI > 40 kg/m2) 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 SORBS3 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 SORBS3 sites using pyrosequencing. This decreased methylation was associated with an increase in SORBS3 gene expression (fold change + 1.7) post-surgery. In addition, we demonstrated that SORBS3 promoter methylation in vitro significantly alters reporter gene expression (P < 0.0001). Two of the SORBS3 methylation sites (Chr.8:22,423,111 and Chr.8:22,423,205) were strongly correlated with fasting plasma glucose levels (r = 0.9, P = 0.00009 and r = 0.8, P = 0.0010). Changes in SORBS3 gene expression post-surgery were correlated with obesity measures and fasting insulin levels (r = 0.5 to 0.8; P < 0.05).ConclusionsThese results demonstrate that SORBS3 methylation and gene expression are altered in obesity and restored to normal levels through weight loss induced by RYGB surgery.

Obesity-Related Epigenetic Changes After Bariatric Surgery

“…These changes after bariatric surgery were also associated with changes in the transcript levels, suggesting that these weight loss-induced epigenetic changes play a role in the regulation of metabolic gene transcription loss (88). A recent study demonstrated that weight loss induced by RYGB surgery is able to restored to normal levels the SORBS3 methylation and gene expression in the muscle (91). Alterations in the expression and methylation patterns of genes involved in insulin signaling as well as those related to specific non-alcoholic fatty liver disease (NAFLD) were also observed in liver biopsies after bariatric surgery (92).…”

Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction

“…In skeletal muscle biopsies 6 mo after surgery, gastric bypass patients had normalized DNA methylation in 11 metabolic gene promoters, including PDK4, peroxisome proliferator-activated receptor γ coactivator 1 α (PPARGC1A), pyruvate dehydrogenase E1 α 1 subunit (PDHA1), myosin heavy chain 2 (MYH2), acyl-CoA oxidase 1 (ACOX1), and others (46). Another study found reduced methylation in skeletal muscle at 30 CpGs associated with sorbin and SH3 domain containing 3 (SORBS3) after Rouxen-Y gastric bypass surgery (47). In addition to muscle, DNA methylation profiles of omentum and subcutaneous adipose tissue were altered by gastric bypass surgery (48).…”

Epigenetyczna regulacja ekspresji genów – nowy mechanizm łączący otyłość z rozwojem cukrzycy typu 2

“…Improved metabolic performance was associated with an increase in PPARGC1A expression, resulting from a decrease in PPARGC1A promoter region methylation [57]. Another recent study found that sorbin and SH3 domain containing 3 (SORBS3) expression in skeletal muscle was regulated by the methylation of its promoter region, altered in obesity, and restored to normal levels through gastric bypass surgery-induced weight loss [58]. Previous studies found that SORBS3 gene expression was significantly associated with BMI, percent body fat, and fasting insulin and glucose levels [58].…”

“…Another recent study found that sorbin and SH3 domain containing 3 (SORBS3) expression in skeletal muscle was regulated by the methylation of its promoter region, altered in obesity, and restored to normal levels through gastric bypass surgery-induced weight loss [58]. Previous studies found that SORBS3 gene expression was significantly associated with BMI, percent body fat, and fasting insulin and glucose levels [58]. Collectively, the post-surgery data furthered our understanding of changes in DNA methylation that is associated with obesity and T2D.…”