Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients

Henriette Kirchner, Indranil Sinha, Hui Gao, Maxwell A Ruby, Milena Schönke, Jessica M Lindvall, Romain Barrès, Anna Krook, Erik Näslund, Karin Dahlman-Wright, Juleen R Zierath

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Abstract

OBJECTIVE: Epigenetic modifications contribute to the etiology of type 2 diabetes. 

METHOD: 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. 

RESULT: 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. 

CONCLUSION: 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.

Original languageEnglish
Pages (from-to)171-183
Number of pages13
JournalMolecular Metabolism
Volume5
Issue number3
Early online date2 Jan 2016
DOIs
Publication statusPublished - Mar 2016
Externally publishedYes

Keywords

  • Liver
  • Obesity
  • Type 2 Diabetes
  • Epigenetics
  • Lipid
  • Glucose

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