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) | 171-183 |
| Number of pages | 13 |
| ISSN | 2212-8778 |
| DOIs | |
| Publication status | Published - 01.03.2016 |
Funding
The authors thank Dr. Carsten Daub from SciLifeLab, Science for Life Laboratory, Solna, Sweden and Rasmus Sjögren, Karolinska Institutet, for their advice regarding the genome-wide data analysis. H.K. is supported by an EMBO long-term fellowship. This work was supported by grants from the Thurings Stiftelse, The Tore Nilson Stiftelse, The 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 ), and Stockholm County Council ( 2012-0086 ) supported this research. Gene expression profiling and DNA-methylation assays were performed at the Bioinformatics and Expression Analysis core facility ( www.bea.ki.se ). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Foundation ( www.metabol.ku.dk ).
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
