An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss

Benton, Miles C.; Johnstone, Alice; Eccles, David; Harmon, Brennan; Hayes, Mark; Lea, Rodney Arthur; Griffiths, Lyn R.; Hoffman, Eric P.; Stubbs, Richard S.; Macartney-Coxson, Donia

doi:10.1186/s13059-014-0569-x

Cited by 220 publications

(212 citation statements)

References 118 publications

(147 reference statements)

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“…However, after correction for multiple testing, Arner and colleagues were unable to find significant associations between the investigated methylation sites and insulin resistance in this cohort. Nevertheless, they present thousands of differentially methylated sites based on a nominal association, and validate their results by showing that some of them are also found in similar studies of DNA methylation in adipose tissue related to BMI, type 2 diabetes or weight loss [6,[9][10][11]. For example, 591 differentially methylated sites identified in adipose tissue of individuals with type 2 diabetes compared with nondiabetic controls in a study by Nilsson et al were also found to be nominally associated with insulin resistance in the study by Arner et al [6,9].…”

Section: Dnmt Dna (Cytosine-5)-methyltransferase Pbmc Peripheral Bloomentioning

confidence: 94%

“…Since the insulin-resistant women in the Arner et al study also have a higher BMI, it is difficult to conclude whether these 1973 sites are primarily associated with higher BMI rather than insulin sensitivity. It should also be noted that Arner et al found 91 differentially methylated sites that overlapped with sites that changed methylation in adipose tissue after weight loss induced by bariatric surgery [6,11]. Whether differential methylation of these sites contributes to improved insulin sensitivity needs to be further tested.…”

Section: Dnmt Dna (Cytosine-5)-methyltransferase Pbmc Peripheral Bloomentioning

confidence: 99%

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Epigenetic markers to further understand insulin resistance

Ling

Rönn

2016

Diabetologia

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Epigenetic variation in human adipose tissue has been linked to type 2 diabetes and its related risk factors including age and obesity. Insulin resistance, a key risk factor for type 2 diabetes, may also be associated with altered DNA methylation in visceral and subcutaneous adipose tissue. Furthermore, linking epigenetic variation in target tissues to similar changes in blood cells may identify new blood-based biomarkers. In this issue of Diabetologia, Arner et al studied the transcriptome and methylome in subcutaneous and visceral adipose tissue of 80 obese women who were either insulin-sensitive or -resistant (DOI 10.1007/s00125-016-4074-5). While they found differences in gene expression between the two groups, no alterations in DNA methylation were found after correction for multiple testing. Nevertheless, based on nominal p values, their methylation data overlapped with methylation differences identified in adipose tissue of individuals with type 2 diabetes compared with healthy individuals. Differential methylation of these overlapping CpG sites may predispose to diabetes by occurring already in the insulin-resistant state. Furthermore, some methylation changes may contribute to an inflammatory process in adipose tissue since the identified CpG sites were annotated to genes encoding proteins involved in inflammation. Finally, the methylation pattern in circulating leucocytes did not mirror the adipose tissue methylome of these 80 women. Together, identifying novel molecular mechanisms contributing to insulin resistance and type 2 diabetes may help advance the search for new therapeutic alternatives. Insulin resistance is a condition where the cellular response to insulin is impaired, resulting in elevated insulin levels in the fasting state, although glucose levels are normal or elevated. It affects multiple tissues and is believed to be an underlying cause of type 2 diabetes. It is also a contributing factor for cardiovascular diseases, explained by the association with, for example, obesity, hypertension and dyslipidaemia [1]. Thereby, to prevent and treat many of our global metabolic diseases, we need to further understand insulin resistance on a molecular level.As insulin resistance is caused by multiple factors and affects multiple tissues, there is a need to investigate the interactions between, for example, genetic and non-genetic factors and between different tissues. Epigenetic mechanisms, including DNA methylation, are strong candidates for mediating the environmental effect on the genome and are linked to gene activity and function [2]. In differentiated human cells, DNA methylation mainly takes place on a cytosine residue followed by guanine, a so called CpG site. Key enzymes regulating DNA methylation include DNA (cytosine-5)-methyltransferase (DNMT)3A and -3B, which are involved in de novo methylation, as well as DNMT1, which copies the methylation patterns during replication. In addition, the ten-eleven translocation (TET) enzymes were found to be involved in active demethylation b...

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Section: Dnmt Dna (Cytosine-5)-methyltransferase Pbmc Peripheral Bloomentioning

confidence: 94%

Section: Dnmt Dna (Cytosine-5)-methyltransferase Pbmc Peripheral Bloomentioning

confidence: 99%

Epigenetic markers to further understand insulin resistance

Ling

Rönn

2016

Diabetologia

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“…35 The corresponding genes POLK for cg05673882 and ALPP for cg23667432 are oncogenes that play roles in the formation of several age-related cancers, including breast, prostate, lung, and ovarian cancers. [36][37][38][39] The biologic functions of the remaining 3 loci within unassigned genome regions are not yet known, only locus cg01127300 has been disclosed as a potential epigenetic regulator of obesity, 40 one of the deficits of the frailty syndrome. 41 Interestingly, neither of the most strongly smoking-related CpG sites, cg05575921 (AHRR) or cg03636183 (F2RL3), 26 was identified to be related to the FI in the present study.…”

Section: Discussionmentioning

confidence: 99%

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

et al. 2017

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Tobacco smoking is a preventable environmental factor that contributes to a wide spectrum of age-related health outcomes; however, its association with the development of frailty is not yet well established. We examined the associations of self-reported smoking indicators, serum cotinine levels and smoking-related DNA methylation biomarkers with a quantitative frailty index (FI) in 2 independent subsets of older adults (age 50-75) recruited in Saarland, Germany in 2000 -2002 (discovery set: n D 978, validation set: n D 531). We obtained DNA methylation profiles in whole blood samples by Illumina HumanMethylation450 BeadChip and calculated the FI according to the method of Mitnitski and Rockwood. Mixed linear regression models were implemented to assess the associations between smoking indicators and the FI. After controlling for potential covariates, current smoking, cumulative smoking exposure (pack-years), and time after smoking cessation (years) were significantly associated with the FI (P-value < 0.05). In the discovery panel, 17 out of 151 previously identified smoking-related CpG sites were associated with the FI after correction for multiple testing (FDR < 0.05). Nine of them survived in the validation phase and were designated as frailty-associated loci. A smoking index (SI) based on the 9 loci manifested a monotonic association with the FI. In conclusion, this study suggested that epigenetic alterations could play a role in smoking-associated development of frailty. The identified CpG sites have the potential to be prognostic biomarkers of frailty and frailty-related health outcomes. Our findings and the underlying mechanisms should be followed up in further, preferably longitudinal studies.

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“…10 In addition, EWAS have been conducted to investigate associations of body mass index (BMI) or birth weight with DNA methylation in one tissue such as blood, and the candidate CpG sites were further examined in another tissue such as adipose tissue. [11][12][13][14][15][16] Several epigenetic biomarkers associated with BMI were identified, such as DNA methylation of HIF3A. 13 Some studies showed that corresponding methylation markers in peripheral blood have consistent associations as those discovered in adipose tissue.…”

Section: Introductionmentioning

confidence: 99%

Epigenome-wide profiling of DNA methylation in paired samples of adipose tissue and blood

et al. 2016

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Many epigenetic association studies have attempted to identify DNA methylation markers in blood that are able to mirror those in target tissues. Although some have suggested potential utility of surrogate epigenetic markers in blood, few studies have collected data to directly compare DNA methylation across tissues from the same individuals. Here, epigenomic data were collected from adipose tissue and blood in 143 subjects using Illumina HumanMethylation450 BeadChip array. The top axis of epigenome-wide variation differentiates adipose tissue from blood, which is confirmed internally using cross-validation and externally with independent data from the two tissues. We identified 1,285 discordant genes and 1,961 concordant genes between blood and adipose tissue. RNA expression data of the two classes of genes show consistent patterns with those observed in DNA methylation. The discordant genes are enriched in biological functions related to immune response, leukocyte activation or differentiation, and blood coagulation. We distinguish the CpG-specific correlation from the within-subject correlation and emphasize that the magnitude of within-subject correlation does not guarantee the utility of surrogate epigenetic markers. The study reinforces the critical role of DNA methylation in regulating gene expression and cellular phenotypes across tissues, and highlights the caveats of using methylation markers in blood to mirror the corresponding profile in the target tissue.

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An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss

Cited by 220 publications

References 118 publications

Epigenetic markers to further understand insulin resistance

Epigenetic markers to further understand insulin resistance

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

Epigenome-wide profiling of DNA methylation in paired samples of adipose tissue and blood

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