title: Weight loss after gastric bypass surgery in human obesity remodels promoter methylation.
abstract: DNA methylation provides a mechanism by which environmental factors can control insulin sensitivity in obesity. Here, we assessed DNA methylation in skeletal muscle from obese people before and after Roux-en-Y gastric bypass (RYGB). Obesity was associated with altered expression of a subset of genes enriched in metabolic process and mitochondrial function. After weight loss, the expression of the majority of the identified genes was normalized to levels observed in normal-weight, healthy controls. Among the 14 metabolic genes analyzed, promoter methylation of 11 genes was normalized to levels observed in the normal-weight, healthy subjects. Using bisulfite sequencing, we show that promoter methylation of PGC-1α and PDK4 is altered with obesity and restored to nonobese levels after RYGB-induced weight loss. A genome-wide DNA methylation analysis of skeletal muscle revealed that obesity is associated with hypermethylation at CpG shores and exonic regions close to transcription start sites. Our results provide evidence that obesity and RYGB-induced weight loss have a dynamic effect on the epigenome.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Romain
authors.initials: R
authors.lastname: Barres
authors.forename: Henriette
authors.initials: H
authors.lastname: Kirchner
authors.forename: Morten
authors.initials: M
authors.lastname: Rasmussen
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.forename: Francisc R
authors.initials: FR
authors.lastname: Kantor
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
mesh_terms: D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015390:Gastric Bypass; D015894:Genome, Human; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D024363:Transcription Initiation Site; D059467:Transcriptome; D015431:Weight Loss
chemical_list: C000631432:PDK4 protein, human; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases