Weight loss after Roux-En-Y gastric bypass surgery reveals skeletal muscle DNA methylation changes

Clinical Epigenetics

Eleanna De Filippis¹  Lori R. Roust¹  Tonya R. Benjamin¹  Lawrence J. Mandarino²  Richard L. Coletta²  Luis A. Garcia²  Baltazar Campos²  Dawn K. Coletta³  James A. Madura⁴  Samantha E. Day⁵ 

[1] Department of Endocrinology, Metabolism and Diabetes, Mayo Clinic Arizona, Scottsdale, AZ, USA;Department of Medicine, Division of Endocrinology, The University of Arizona College of Medicine, PO Box 245035, 1501 N. Campbell Ave, 85724-5035, Tucson, AZ, USA;Department of Medicine, Division of Endocrinology, The University of Arizona College of Medicine, PO Box 245035, 1501 N. Campbell Ave, 85724-5035, Tucson, AZ, USA;Department of Physiology, The University of Arizona College of Medicine, Tucson, AZ, USA;Mayo Clinic Hospital, Phoenix, AZ, USA;Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA;

关键词: DNA methylation;    Next generation sequencing;    Skeletal muscle;    Obesity;    Bariatric surgery;   

DOI  :  10.1186/s13148-021-01086-6

来源: Springer

【 摘 要 】

BackgroundThe mechanisms of weight loss and metabolic improvements following bariatric surgery in skeletal muscle are not well known; however, epigenetic modifications are likely to contribute. The aim of our study was to investigate skeletal muscle DNA methylation after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Muscle biopsies were obtained basally from seven insulin-resistant obese (BMI > 40 kg/m2) female subjects (45.1 ± 3.6 years) pre- and 3-month post-surgery with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. Four lean (BMI < 25 kg/m2) females (38.5 ± 5.8 years) served as controls. We performed reduced representation bisulfite sequencing next generation methylation on DNA isolated from the vastus lateralis muscle biopsies.ResultsGlobal methylation was significantly higher in the pre- (32.97 ± 0.02%) and post-surgery (33.31 ± 0.02%) compared to the lean (30.46 ± 0.02%), P < 0.05. MethylSig analysis identified 117 differentially methylated cytosines (DMCs) that were significantly altered in the post- versus pre-surgery (Benjamini–Hochberg q < 0.05). In addition, 2978 DMCs were significantly altered in the pre-surgery obese versus the lean controls (Benjamini–Hochberg q < 0.05). For the post-surgery obese versus the lean controls, 2885 DMCs were altered (Benjamini–Hochberg q < 0.05). Seven post-surgery obese DMCs were normalized to levels similar to those observed in lean controls. Of these, 5 were within intergenic regions (chr11.68,968,018, chr16.73,100,688, chr5.174,115,531, chr5.1,831,958 and chr9.98,547,011) and the remaining two DMCs chr17.45,330,989 and chr14.105,353,824 were within in the integrin beta 3 (ITGB3) promoter and KIAA0284 exon, respectively. ITGB3 methylation was significantly decreased in the post-surgery (0.5 ± 0.5%) and lean controls (0 ± 0%) versus pre-surgery (13.6 ± 2.7%, P < 0.05). This decreased methylation post-surgery was associated with an increase in ITGB3 gene expression (fold change + 1.52, P = 0.0087). In addition, we showed that ITGB3 promoter methylation in vitro significantly suppressed transcriptional activity (P < 0.05). Transcription factor binding analysis for ITGB3 chr17.45,330,989 identified three putative transcription factor binding motifs; PAX-5, p53 and AP-2alphaA.ConclusionsThese results demonstrate that weight loss after RYGB alters the epigenome through DNA methylation. In particular, this study highlights ITGB3 as a novel gene that may contribute to the metabolic improvements observed post-surgery. Future additional studies are warranted to address the exact mechanism of ITGB3 in skeletal muscle.

【 授权许可】

CC BY