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 (SORBS3) 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 SORBS3 with obesity (BMI > 30 kg/m(2)) compared to lean controls. In the present study, basal muscle biopsies were obtained from seven morbidly obese (BMI > 40 kg/m(2)) female subjects pre-and3months 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). Conclusions: These results demonstrate that SORBS3 methylation and gene expression are altered in obesity and restored to normal levels through weight loss induced by RYGB surgery.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/625740 |
| Date | 02 September 2017 |
| Creators | Day, Samantha E., Garcia, Luis A., Coletta, Richard L., Campbell, Latoya E., Benjamin, Tonya R., De Filippis, Elena A., Madura, James A., Mandarino, Lawrence J., Roust, Lori R., Coletta, Dawn K. |
| Contributors | Univ Arizona, Coll Med, Dept Med, Univ Arizona, Coll Med Phoenix, Dept Basic Med Sci |
| Publisher | BIOMED CENTRAL LTD |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License. |
| Relation | http://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-017-0396-5 |
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