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

TY - JOUR

T1 - Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients

AU - Kirchner, Henriette

AU - Sinha, Indranil

AU - Gao, Hui

AU - Ruby, Maxwell A

AU - Schönke, Milena

AU - Lindvall, Jessica M

AU - Barrès, Romain

AU - Krook, Anna

AU - Näslund, Erik

AU - Dahlman-Wright, Karin

AU - Zierath, Juleen R

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.molmet.2015.12.004

DO - 10.1016/j.molmet.2015.12.004

M3 - Journal article

C2 - 26977391

SN - 2212-8778

VL - 5

SP - 171

EP - 183

JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 3

ER -