title: The epigenetic signature of systemic insulin resistance in obese women.
abstract: Insulin resistance (IR) links obesity to type 2 diabetes. The aim of this study was to explore whether white adipose tissue (WAT) epigenetic dysregulation is associated with systemic IR by genome-wide CG dinucleotide (CpG) methylation and gene expression profiling in WAT from insulin-resistant and insulin-sensitive women. A secondary aim was to determine whether the DNA methylation signature in peripheral blood mononuclear cells (PBMCs) reflects WAT methylation and, if so, can be used as a marker for systemic IR.
  
  
  
  From 220 obese women, we selected a total of 80 individuals from either of the extreme ends of the distribution curve of HOMA-IR, an indirect measure of systemic insulin sensitivity. Genome-wide transcriptome and DNA CpG methylation profiling by array was performed on subcutaneous (SAT) and visceral (omental) adipose tissue (VAT). CpG methylation in PBMCs was assayed in the same cohort.
  
  
  
  There were 647 differentially expressed genes (false discovery rate [FDR] 10%) in SAT, all of which displayed directionally consistent associations in VAT. This suggests that IR is associated with dysregulated expression of a common set of genes in SAT and VAT. The average degree of DNA methylation did not differ between the insulin-resistant and insulin-sensitive group in any of the analysed tissues/cells. There were 223 IR-associated genes in SAT containing a total of 336 nominally significant differentially methylated sites (DMS). The 223 IR-associated genes were over-represented in pathways related to integrin cell surface interactions and insulin signalling and included COL5A1, GAB1, IRS2, PFKFB3 and PTPRJ. In VAT there were a total of 51 differentially expressed genes (FDR 10%); 18 IR-associated genes contained a total of 29 DMS.
  
  
  
  In individuals discordant for insulin sensitivity, the average DNA CpG methylation in SAT and VAT is similar, although specific genes, particularly in SAT, display significantly altered expression and DMS in IR, possibly indicating that epigenetic regulation of these genes influences metabolism.
authors.affiliation: Department of Medicine, Karolinska Institutet, Karolinska University Hospital, C2:94, Huddinge, S-141 86, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.affiliation: GlaxoSmithKline R&D, Stevenage, UK.
authors.forename: Anna-Stina
authors.initials: AS
authors.lastname: Sahlqvist
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Indranil
authors.initials: I
authors.lastname: Sinha
authors.affiliation: GlaxoSmithKline R&D, Research Triangle Park, NC, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Computational and Systems Biology, Discovery Sciences, Janssen Pharmaceutical, Research & Development, LLC, San Diego, CA, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yao
authors.affiliation: GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Waterworth
authors.affiliation: GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Rajpal
authors.affiliation: Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: A Katrina
authors.initials: AK
authors.lastname: Loomis
authors.affiliation: GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Freudenberg
authors.affiliation: GlaxoSmithKline R&D, Stevenage, UK.
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.affiliation: Department of Surgery, Ersta Hospital, Stockholm, Sweden.|Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Danderyd, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Thorell
authors.affiliation: Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Danderyd, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.affiliation: Department of Medicine, Karolinska Institutet, Karolinska University Hospital, C2:94, Huddinge, S-141 86, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Ryden
authors.affiliation: Department of Medicine, Karolinska Institutet, Karolinska University Hospital, C2:94, Huddinge, S-141 86, Stockholm, Sweden. ingrid.dahlman@ki.se.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dahlman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D052436:Adipose Tissue, White / Q000378:metabolism; D000328:Adult; D024062:Collagen Type V / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D050152:Intra-Abdominal Fat / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D025481:Phosphofructokinase-2 / Q000235:genetics; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530725:COL5A1 protein, human; D024062:Collagen Type V; C098587:GAB1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; C486288:PTPRJ protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
keywords: CpG island; DNA methylation; Visceral adipose tissue