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[superscript 2]) compared to lean controls. In the present study, basal muscle biopsies were obtained from seven morbidly obese (BMI > 40 kg/m[superscript 2]) 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).
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.
Details
- Alterations of Sorbin and SH3 Domain Containing 3 (SORBS3) in Human Skeletal Muscle Following Roux-en-Y Gastric Bypass Surgery
- Day, Samantha (Author)
- Garcia, Luis A. (Author)
- Coletta, Richard L. (Author)
- Campbell, Latoya (Author)
- Benjamin, Tonya R. (Author)
- De Filippis, Elena A. (Author)
- Madura, James A. (Author)
- Mandarino, Lawrence J. (Author)
- Roust, Lori R. (Author)
- Coletta, Dawn K. (Author)
- College of Liberal Arts and Sciences (Contributor)
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Digital object identifier: 10.1186/s13148-017-0396-5
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Identifier TypeInternational standard serial numberIdentifier Value1868-7083
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The electronic version of this article is the complete one and can be found online at: https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-017-0396-5
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Day, S. E., Garcia, L. A., Coletta, R. L., Campbell, L. E., Benjamin, T. R., Filippis, E. A., . . . Coletta, D. K. (2017). Alterations of sorbin and SH3 domain containing 3 (SORBS3) in human skeletal muscle following Roux-en-Y gastric bypass surgery. Clinical Epigenetics, 9(1). doi:10.1186/s13148-017-0396-5