title: The fat cell epigenetic signature in post-obese women is characterized by global hypomethylation and differential DNA methylation of adipogenesis genes.
abstract: OBJECTIVE
  Obese subjects have increased number of enlarged fat cells that are reduced in size but not in number in post-obesity. We performed DNA methylation profiling in fat cells with the aim of identifying differentially methylated DNA sites (DMS) linked to adipose hyperplasia (many small fat cells) in post-obesity.
  
  
  METHODS
  Genome-wide DNA methylation was analyzed in abdominal subcutaneous fat cells from 16 women examined 2 years after gastric bypass surgery at a post-obese state (body mass index (BMI) 26±2 kg m(-2), mean±s.d.) and from 14 never-obese women (BMI 25±2 kg m(-2)). Gene expression was analyzed in subcutaneous adipose tissue from nine women in each group. In a secondary analysis, we examined DNA methylation and expression of adipogenesis genes in 15 and 11 obese women, respectively.
  
  
  RESULTS
  The average degree of DNA methylation of all analyzed CpG sites was lower in fat cells from post-obese as compared with never-obese women (P=0.014). A total of 8504 CpG sites were differentially methylated in fat cells from post-obese versus never-obese women (false discovery rate 1%). DMS were under-represented in CpG islands and surrounding shores. The 8504 DMS mapped to 3717 unique genes; these genes were over-represented in cell differentiation pathways. Notably, 27% of the genes linked to adipogenesis (that is, 35 of 130) displayed DMS (adjusted P=10(-8)) in post-obese versus never-obese women. Next, we explored DNA methylation and expression of genes linked to adipogenesis in more detail in adipose tissue samples. DMS annotated to adipogenesis genes were not accompanied by differential gene expression in post-obese compared with never-obese women. In contrast, adipogenesis genes displayed differential DNA methylation accompanied by altered expression in obese women.
  
  
  CONCLUSIONS
  Global CpG hypomethylation and over-representation of DMS in adipogenesis genes in fat cells may contribute to adipose hyperplasia in post-obese women.
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Dahlman
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Sinha
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Brodin
authors.affiliation: 1] Department of Clinical Sciences, Danderyds Hospital, Karolinska Institutet., Stockholm, Sweden [2] Department of Surgery, Ersta Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Thorell
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Rydén
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: D P
authors.initials: DP
authors.lastname: Andersson
authors.affiliation: 1] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden [2] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: J
authors.initials: J
authors.lastname: Henriksson
authors.affiliation: Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, CRC, Scania University Hospital, Malmo, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Perfilyev
authors.affiliation: Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, CRC, Scania University Hospital, Malmo, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Ling
authors.affiliation: 1] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden [2] SciLifeLab, Science for Life Laboratory, Solna, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Dahlman-Wright
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Arner
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics*; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D015992:Body Mass Index; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015390:Gastric Bypass; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results; D050151:Subcutaneous Fat / Q000378:metabolism*; D013548:Sweden / Q000453:epidemiology; D015430:Weight Gain / Q000235:genetics; D015431:Weight Loss
chemical_list: D015415:Biomarkers