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

Research output: Contribution to journal › Article › peer-review

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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
Pages (from-to)	171-183
Number of pages	13
Journal	Molecular Metabolism
Volume	5
Issue number	3
Early online date	2 Jan 2016
DOIs	https://doi.org/10.1016/j.molmet.2015.12.004
Publication status	Published - Mar 2016
Externally published	Yes

Keywords

Liver
Obesity
Type 2 Diabetes
Epigenetics
Lipid
Glucose

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.molmet.2015.12.004Licence: CC BY-NC-ND

Published manuscript
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Final published version, 2.55 MBLicence: CC BY-NC-ND

Cite this

@article{ff88abe1c6f8470597710c3a975a0e1f,

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.",

keywords = "Liver, Obesity, Type 2 Diabetes, Epigenetics, Lipid, Glucose",

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",

month = mar,

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

language = "English",

volume = "5",

pages = "171--183",

journal = "Molecular Metabolism ",

issn = "2212-8778",

publisher = "Elsevier",

number = "3",

}

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

Y1 - 2016/3

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.

KW - Liver

KW - Obesity

KW - Type 2 Diabetes

KW - Epigenetics

KW - Lipid

KW - Glucose

U2 - 10.1016/j.molmet.2015.12.004

DO - 10.1016/j.molmet.2015.12.004

M3 - Article

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VL - 5

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JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

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