title: Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects.
abstract: 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.
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain; Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain. Electronic address: anabelencrujeiras@hotmail.com.
authors.forename: A B
authors.initials: AB
authors.lastname: Crujeiras
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Diaz-Lagares
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), Madrid, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Moreno-Navarrete
authors.affiliation: Laboratory of Personalized Medicine, Epigenomics Unit, Medical Research Institute La Fe, Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Sandoval
authors.affiliation: Biostatistics Unit, Medical Research Institute La Fe, Valencia, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Hervas
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), Madrid, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: W
authors.initials: W
authors.lastname: Ricart
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: F F
authors.initials: FF
authors.lastname: Casanueva
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; Passeig de Lluís Companys, 23, Barcelona, Catalonia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), Madrid, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain. Electronic address: jmfreal@idibgi.org.
authors.forename: J M
authors.initials: JM
authors.lastname: Fernandez-Real
mesh_terms: D000886:Anthropometry; D002877:Chromosomes, Human / Q000235:genetics; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015894:Genome, Human; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics*; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000235:genetics*; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D007328:Insulin; D014157:Transcription Factors; C581787:ZNF714 protein, human