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

Crujeiras, Ana B.; Díaz‐Lagares, Ángel; Moreno-Navarrete, José María; Sandoval, Juan; Hervás, David; Gómez, Antonio; Ricart, Wifredo; Casanueva, Felipe F.; Esteller, Manel; Fernández‐Real, José‐Manuel

doi:10.1016/j.trsl.2016.07.002

Cited by 76 publications

(69 citation statements)

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“…It has been shown that DNA methylation can be influenced by environmental and lifestyle factors, including smoking and unhealthy diet [14,15]. Also, alterations in DNA methylation levels have been shown to be a consequence of increased adiposity [16] and this epigenetic mechanism was proposed as a potential link between obesity and its comorbidities such as insulin resistance [17] and cancer [18,19]. Therefore, we hypothesized that weight loss resulting from bariatric surgery may lead to changes in DNA methylation profiles, potentially providing insight into molecular mechanisms underlying weight loss-induced metabolic improvement.…”

Section: Introductionmentioning

confidence: 99%

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

et al. 2020

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Background: Severe obesity is a growing, worldwide burden and conventional therapies including radical change of diet and/or increased physical activity have limited results. Bariatric surgery has been proposed as an alternative therapy showing promising results. It leads to substantial weight loss and improvement of comorbidities such as type 2 diabetes. Increased adiposity is associated with changes in epigenetic profile, including DNA methylation. We investigated the effect of bariatric surgery on clinical profile, DNA methylation, and biological age estimated using Horvath's epigenetic clock. Results:To determine the impact of bariatric surgery and subsequent weight loss on clinical traits, a cohort of 40 severely obese individuals (BMI = 30-73 kg/m 2 ) was examined at the time of surgery and at three follow-up visits, i.e., 3, 6, and 12 months after surgery. The majority of the individuals were women (65%) and the mean age at surgery was 45.1 ± 8.1 years. We observed a significant decrease over time in BMI, fasting glucose, HbA1c, HOMA-IR, insulin, total cholesterol, triglycerides, LDL and free fatty acids levels, and a significant small increase in HDL levels (all p values < 0.05). Epigenome-wide association analysis revealed 4857 differentially methylated CpG sites 12 months after surgery (at Bonferroni-corrected p value < 1.09 × 10 −7 ). Including BMI change in the model decreased the number of significantly differentially methylated CpG sites by 51%. Gene set enrichment analysis identified overrepresentation of multiple processes including regulation of transcription, RNA metabolic, and biosynthetic processes in the cell. Bariatric surgery in severely obese patients resulted in a decrease in both biological age and epigenetic age acceleration (EAA) (mean = − 0.92, p value = 0.039). Conclusions: Our study shows that bariatric surgery leads to substantial BMI decrease and improvement of clinical outcomes observed 12 months after surgery. These changes explained part of the association between bariatric surgery and DNA methylation. We also observed a small, but significant improvement of biological age. These epigenetic changes may be modifiable by environmental lifestyle factors and could be used as potential biomarkers for obesity and in the future for obesity related comorbidities.

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Section: Introductionmentioning

confidence: 99%

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

et al. 2020

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“…Of these sites, 538 were associated with unique genes with functions in cell adhesion, signal transduction and regulation of transcription and include ADAM2, IGF2BP1, TBX5, HDACM, CD44 and ZNF711. These data are supportive of the close link between obesity and T2D and suggest the existence of a methylome map within Visceral adipose tissue (VAT) that may predispose individuals to IR and T2D [38].…”

Section: Human Epigenome-wide Association Studiesmentioning

confidence: 64%

“…Likewise, human ataxin-2 (ATXN2) knock-out mice display obesity, insulin resistance and dyslipidemia [37]. To understand the effects of the loss of ATXN2, Meierhofer and team used unbiased profiling approaches to quantify the global metabolome of ATXN2 knock-out mice with label-free mass spectrometry [38]. Significant down-regulated pathways for branched chain and other amino acid metabolism, fatty acids and citric acid cycle provided evidence for the biological function of ATXN2 and the potential mechanism via which the lean phenotype is maintained [38].…”

Section: Metabolomic and Obesity In Animal Modelsmentioning

confidence: 99%

“…To understand the effects of the loss of ATXN2, Meierhofer and team used unbiased profiling approaches to quantify the global metabolome of ATXN2 knock-out mice with label-free mass spectrometry [38]. Significant down-regulated pathways for branched chain and other amino acid metabolism, fatty acids and citric acid cycle provided evidence for the biological function of ATXN2 and the potential mechanism via which the lean phenotype is maintained [38]. Thus, metabolomics used in combination with genetic models offers a viable way to determine biological significance of genes and improve understanding of cellular pathways.…”

Section: Metabolomic and Obesity In Animal Modelsmentioning

confidence: 99%

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The Omics of Obesity

Henstridge¹,

Bozaoglu²

2017

Adiposity - Omics and Molecular Understanding

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Obesity is a complex multi-faceted disease affecting billions of people worldwide. Traditionally, obesity was thought to be a consequence of having access to energy dense food and busy lifestyles that do not factor in sufficient physical activity. Although diet and exercise play a major role in obesity development, these are not the only contributors. It is widely accepted that genetic and epigenetic factors also play a major role in obesity development and these in turn affect the lipidome, metabolome and proteome. With new technological advances, it is now possible to delve into these specific areas to further understand the mechanisms involved in obesity development. These technologies are collectively termed "omics" technologies, and this chapter will summarise the recent advances in obesity and metabolism research and describe new technologies that have been used to identify mechanisms that play a major role in the development of obesity. In particular, we will examine the different omics platforms that are available and have been used to study obesity. Collectively, these studies will be fundamental in identifying new and effective treatment strategies.

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“…Notably, PM is also implicated not only in the pathogenesis of T2D but also in cancer development complicated with T2D [24][25][26] . We previously demonstrated that enhanced PM of CDH1 in long-term T2D is associated with poor prognosis of pancreatic ductal cancer (PDC) 26 .…”

mentioning

confidence: 99%

Diabetes, an independent poor prognostic factor of non-B non-C hepatocellular carcinoma, correlates with dihydropyrimidinase-like 3 promoter methylation

Umetsu

Mizukami

Saito

et al. 2020

Sci Rep

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A concurrent increase in the prevalence of hepatocellular carcinoma (HCC) with that of type 2 diabetes (T2D) and obesity has been reported in the absence of hepatitis B virus surface antigen-negative/ hepatitis c virus antibody-negative Hcc (nBnc-Hcc). However, the prognostic relevance of this association remains unclear. Promoter methylation (PM) of the dihydropyrimidinase-like 3 gene (DPYSL3) has been implicated in virus-related HCC. However, it remains unclear whether T2D influences PM in NBNC-HCC. We determined the influence of T2D on clinicopathological profile and PM of DPYSL3 and CDK2NA in patients with nBnc-Hcc who were divided into two groups: non-diabetes (non-DM; n = 46) and diabetes (DM; n = 47). DM was associated with a higher Union for International Cancer control grade, marginal vascular invasion and tumour cell proliferation irrespective of the duration of T2D as well as higher rates of PM of DPYSL3 than non-DM; however, pM of CDK2NA was similar between both groups. pM of DPYSL3 reduced its expression which inversely correlated with reduced patient survival. In conclusion, T2D is associated with poor prognosis of NBNC-HCC in which a high frequency of pM of DPYSL3 may play a pivotal role in its pathogenesis.

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

Cited by 76 publications

References 42 publications

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

The Omics of Obesity

Diabetes, an independent poor prognostic factor of non-B non-C hepatocellular carcinoma, correlates with dihydropyrimidinase-like 3 promoter methylation

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