Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 178; pp. 13 - 24.e5
• Main Authors: Crujeiras, A.B., Diaz-Lagares, A., Moreno-Navarrete, J.M., Sandoval, J., Hervas, D., Gomez, A., Ricart, W., Casanueva, F.F., Esteller, M., Fernandez-Real, J.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2016
• Subjects: Anthropometry; Chromosomes, Human - genetics; Cohort Studies; CpG Islands - genetics; DNA Methylation - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene Expression Regulation - drug effects; Genome, Human; Humans; Insulin - pharmacology; Insulin Resistance - genetics; Internal Medicine; Intra-Abdominal Fat - drug effects; Intra-Abdominal Fat - metabolism; Male; Middle Aged; Obesity, Morbid - genetics; Reproducibility of Results; Transcription Factors - genetics; Transcription Factors - metabolism; DMCpGs; T2D; VAT; GO; IR; IS; HDPP; Human Diabetes Proteome Project; gene ontology; type 2 diabetes; insulin resistant; insulin sensitive; differentially methylated CpG sites; visceral adipose tissue
• ISSN: 1931-5244; 1878-1810; 1878-1810
• DOI: 10.1016/j.trsl.2016.07.002

Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process.