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

doi:10.1016/j.molmet.2015.12.004

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 language	English
Journal	Molecular Metabolism
Volume	5
Issue number	3
Pages (from-to)	171-83
Number of pages	13
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2015.12.004
Publication status	Published - 1 Mar 2016

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Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patientsFinal published version, 2.55 MBLicence: CC BY-NC-ND

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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.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.",

author = "Henriette Kirchner and Indranil Sinha and Hui Gao and Ruby, {Maxwell A} and Milena Sch{\"o}nke and Lindvall, {Jessica M} and Romain Barr{\`e}s and Anna Krook and Erik N{\"a}slund and Karin Dahlman-Wright and Zierath, {Juleen R}",

year = "2016",

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doi = "10.1016/j.molmet.2015.12.004",

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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.

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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 -

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

Abstract

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