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Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes.

ABSTRACT: Failure in glucose response to insulin is a common pathology associated with obesity. In this study, we analyzed the genome wide DNA methylation profile of visceral adipose tissue (VAT) samples in a population of individuals with obesity and assessed whether differential methylation profiles are associated with the presence of type 2 diabetes (T2D).More than 485,000 CpG genome sites from VAT samples from women with obesity undergoing gastric bypass (n = 18), and classified as suffering from type 2 diabetes (T2D) or not (no type 2 diabetes, NT2D), were analyzed using DNA methylation arrays.We found significant differential methylation between T2D and NT2D samples in 24 CpGs that map with sixteen genes, one of which, HOOK2, demonstrated a significant correlation between differentially hypermethylated regions on the gene body and the presence of type 2 diabetes. This was validated by pyrosequencing in a population of 91 samples from both males and females with obesity. Furthermore, when these results were analyzed by gender, female T2D samples were found hypermethylated at the cg04657146-region and the cg 11738485-region of HOOK2 gene, whilst, interestingly, male samples were found hypomethylated in this latter region.The differential methylation profile of the HOOK2 gene in individuals with T2D and obesity might be related to the attendant T2D, but further studies are required to identify the potential role of HOOK2 gene in T2D disease. The finding of gender differences in T2D methylation of HOOK2 also warrants further investigation.

SUBMITTER: Rodriguez-Rodero S

PROVIDER: S-EPMC5724849 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes.

Rodríguez-Rodero Sandra S Menéndez-Torre Edelmiro E Fernández-Bayón Gustavo G Morales-Sánchez Paula P Sanz Lourdes L Turienzo Estrella E González Juan José JJ Martinez-Faedo Ceferino C Suarez-Gutiérrez Lorena L Ares Jessica J Díaz-Naya Lucia L Martin-Nieto Alicia A Fernández-Morera Juan L JL Fraga Mario F MF Delgado-Álvarez Elías E

PloS one 20171211 12

<h4>Aims/hypothesis</h4>Failure in glucose response to insulin is a common pathology associated with obesity. In this study, we analyzed the genome wide DNA methylation profile of visceral adipose tissue (VAT) samples in a population of individuals with obesity and assessed whether differential methylation profiles are associated with the presence of type 2 diabetes (T2D).<h4>Methods</h4>More than 485,000 CpG genome sites from VAT samples from women with obesity undergoing gastric bypass (n = 18 ...[more]

PMID: 29228058

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Project description:BackgroundEpigenetic mechanisms provide an interface between environmental factors and the genome and are known to play a role in complex diseases such as obesity. These mechanisms, including DNA methylation, influence the regulation of development, differentiation and the establishment of cellular identity. Here we employ two approaches to identify differential methylation between two white adipose tissue depots in obese individuals before and after gastric bypass and significant weight loss. We analyse genome-wide DNA methylation data using (a) traditional paired t tests to identify significantly differentially methylated loci (Bonferroni-adjusted P ≤ 1 × 10-7) and (b) novel combinatorial algorithms to identify loci that differentiate between tissue types.ResultsSignificant differential methylation was observed for 3239 and 7722 CpG sites, including 784 and 1129 extended regions, between adipose tissue types before and after significant weight loss, respectively. The vast majority of these extended differentially methylated regions (702) were consistent across both time points and enriched for genes with a role in transcriptional regulation and/or development (e.g. homeobox genes). Other differentially methylated loci were only observed at one time point and thus potentially highlight genes important to adipose tissue dysfunction observed in obesity. Strong correlations (r > 0.75, P ≤ 0.001) were observed between changes in DNA methylation (subcutaneous adipose vs omentum) and changes in clinical trait, in particular for CpG sites within PITX2 and fasting glucose and four CpG sites within ISL2 and HDL. A single CpG site (cg00838040, ATP2C2) gave strong tissue separation, with validation in independent subcutaneous (n = 681) and omental (n = 33) adipose samples.ConclusionsThis is the first study to report a genome-wide DNA methylome comparison of subcutaneous abdominal and omental adipose before and after weight loss. The combinatorial approach we utilised is a powerful tool for the identification of methylation loci that strongly differentiate between these tissues. This study provides a solid basis for future research focused on the development of adipose tissue and its potential dysfunction in obesity, as well as the role DNA methylation plays in these processes.

Project description:The risk of obesity (OB) in adulthood is strongly influenced by maternal body composition. Here we examined the hypothesis that maternal OB influences white adipose tissue (WAT) transcriptome and increases propensity for adipogenesis in the offspring, prior to the development of OB, using an established model of long-term metabolic programming. Employing an overfeeding-based rat model, in which exposure to OB is limited to preconception and gestation alone, we conducted global transcriptomic profiling in WAT, and gene/protein expression analysis of lipogenic and adipogenic pathways and examined adipogenic differentiation of WAT stromal-vascular cells ex vivo. Using reduced representation bisulfite sequencing we also evaluated genome-scale changes in DNA methylation in offspring WAT. Maternal OB led to extensive changes in expression of genes (± 1.8-fold, P ? .05), revealing a distinct up-regulation of lipogenic pathways in WAT. mRNA expression of a battery of sterol regulatory element-binding protein-1-regulated genes was increased in OB-dam offspring, which were confirmed by immunoblotting. In conjunction with lipogenic gene expression, OB-dam offspring showed increased glucose transporter-4 mRNA/protein expression and greater AKT phosphorylation following acute insulin challenge, suggesting sensitization of insulin signaling in WAT. Offspring of OB dams also exhibited increased in vivo expression of adipogenic regulators (peroxisome proliferator-activated receptor-?, CCAAT enhancer binding protein ? [C/EBP-?] and C/EBP-?), associated with greater ex vivo differentiation of WAT stromal-vascular cells. These transcriptomic changes were associated with alterations in DNA methylation of CpG sites and CGI shores, proximal to developmentally important genes, including key pro-adipogenic factors (Zfp423 and C/EBP-?). Our findings strongly suggest that the maternal OB in utero alters adipocyte commitment and differentiation via epigenetic mechanisms.

Project description:BACKGROUNDData from studies conducted in rodent models have shown that decreased adipose tissue (AT) oxygenation is involved in the pathogenesis of obesity-induced insulin resistance. Here, we evaluated the potential influence of AT oxygenation on AT biology and insulin sensitivity in people.METHODSWe evaluated subcutaneous AT oxygen partial pressure (pO2); liver and whole-body insulin sensitivity; AT expression of genes and pathways involved in inflammation, fibrosis, and branched-chain amino acid (BCAA) catabolism; systemic markers of inflammation; and plasma BCAA concentrations, in 3 groups of participants that were rigorously stratified by adiposity and insulin sensitivity: metabolically healthy lean (MHL; n = 11), metabolically healthy obese (MHO; n = 15), and metabolically unhealthy obese (MUO; n = 20).RESULTSAT pO2 progressively declined from the MHL to the MHO to the MUO group, and was positively associated with hepatic and whole-body insulin sensitivity. AT pO2 was positively associated with the expression of genes involved in BCAA catabolism, in conjunction with an inverse relationship between AT pO2 and plasma BCAA concentrations. AT pO2 was negatively associated with AT gene expression of markers of inflammation and fibrosis. Plasma PAI-1 increased from the MHL to the MHO to the MUO group and was negatively correlated with AT pO2, whereas the plasma concentrations of other cytokines and chemokines were not different among the MHL and MUO groups.CONCLUSIONThese results support the notion that reduced AT oxygenation in individuals with obesity contributes to insulin resistance by increasing plasma PAI-1 concentrations and decreasing AT BCAA catabolism and thereby increasing plasma BCAA concentrations.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants K01DK109119, T32HL130357, K01DK116917, R01ES027595, P42ES010337, DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK052574 (Digestive Disease Research Center), and UL1TR002345 (Clinical and Translational Science Award); NIH Shared Instrumentation Grants S10RR0227552, S10OD020025, and S10OD026929; and the Foundation for Barnes-Jewish Hospital.

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Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes.

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Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes.

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