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.
UR - http://www.scopus.com/inward/record.url?scp=84959127723&partnerID=8YFLogxK
U2 - 10.1016/j.molmet.2015.12.004
DO - 10.1016/j.molmet.2015.12.004
M3 - Journal articles
AN - SCOPUS:84959127723
SN - 2212-8778
VL - 5
SP - 171
EP - 183
JO - Molecular Metabolism
JF - Molecular Metabolism
IS - 3
ER -
