title: Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients.
abstract: OBJECTIVE
  Epigenetic modifications contribute to the etiology of type 2 diabetes.
  
  
  METHODS
  We performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing.
  
  
  RESULTS
  We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding.
  
  
  CONCLUSIONS
  Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Henriette
authors.initials: H
authors.lastname: Kirchner
authors.affiliation: Department Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Indranil
authors.initials: I
authors.lastname: Sinha
authors.affiliation: Department Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maxwell A
authors.initials: MA
authors.lastname: Ruby
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Milena
authors.initials: M
authors.lastname: Schönke
authors.affiliation: Department Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Lindvall
authors.affiliation: Section of Integrative Physiology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Romain
authors.initials: R
authors.lastname: Barrès
authors.affiliation: Section of Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.affiliation: Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.affiliation: Department Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; SciLifeLab, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Section of Integrative Physiology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; Section of Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Electronic address: Juleen.zierath@ki.se.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
keywords: Epigenetics; Glucose; Lipid; Liver; Obesity; Type 2 Diabetes