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

Kirchner H, Sinha I, Gao H, Ruby MA, Schönke M, Lindvall JM, Barrès R, Krook A, Näslund E, Dahlman-Wright K, Zierath JR

Mol Metab 5 (3) 171-183 [2016-03-00; online 2016-01-02]

Epigenetic modifications contribute to the etiology of type 2 diabetes. 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. 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. 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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PubMed 26977391

DOI 10.1016/j.molmet.2015.12.004

Crossref 10.1016/j.molmet.2015.12.004

S2212-8778(15)00234-3

pmc PMC4770265