Journal
MOLECULAR METABOLISM
Volume 5, Issue 3, Pages 171-183Publisher
ELSEVIER
DOI: 10.1016/j.molmet.2015.12.004
Keywords
Liver; Obesity; Type 2 Diabetes; Epigenetics; Lipid; Glucose
Categories
Funding
- EMBO
- Thurings Stiftelse
- Tore Nilson Stiftelse
- Strategic Diabetes Program at Karolinska Institutet
- Cardiovascular Research Program at Karolinska Institutet
- European Research Council Ideas Program (ICEBERG) [ERC-2008-AdG23285]
- Swedish Research Council [2011-3550]
- Swedish Diabetes Foundation [DIA2012-082]
- Swedish Foundation for Strategic Research [SRL10-0027]
- Stockholm County Council [2012-0086]
- NNF Center for Basic Metabolic Research [Barres Group] Funding Source: researchfish
- Novo Nordisk Fonden [NNF12OC1016320, NNF14OC0010883, NNF15OC0016536, NNF13OC0005961] Funding Source: researchfish
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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. (C) 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC-BY-NC-ND license (http//creativecommons.org/licenses/by-nc-nd/4.0/)
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