DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity

Abstract

Background Obesity is accompanied by excess adipose fat storage, which may lead to adipose dysfunction, insulin resistance, and type 2 diabetes (T2D). Currently, the tendency to develop T2D in obesity cannot be explained by genetic variation alone—epigenetic mechanisms, such as DNA methylation, might be involved. Here, we aimed to identify changes in DNA methylation and gene expression in visceral adipose tissue (VAT) that might underlie T2D susceptibility in patients with obesity. Methods We investigated DNA methylation and gene expression in VAT biopsies from 19 women with obesity, without (OND = 9) or with T2D (OD = 10). Differences in genome-scale methylation (differentially methylated CpGs [DMCs], false discovery rate < 0.05; and differentially methylated regions [DMRs], p value < 0.05) and gene expression (DEGs, p value <0.05) between groups were assessed. We searched for overlap between altered methylation and expression and the impact of altered DNA methylation on gene expression, using bootstrap Pearson correlation. The relationship of altered DNA methylation to T2D-related traits was also tested. Results We identified 11 120 DMCs and 96 DMRs distributed across all chromosomes, with the greatest density of epigenomic alterations at the MHC locus. These alterations were found in newly and previously T2D-related genes. Several of these findings were supported by validation and extended multi-ethnic analyses. Of 252 DEGs in the OD group, 68 genes contained DMCs (n = 88), of which 24 demonstrated a significant relationship between gene expression and methylation (p values <0.05). Of these, 16, including ATP11A, LPL and EHD2 also showed a significant correlation with fasting glucose and HbA1c levels. Conclusions Our results revealed novel candidate genes related to T2D pathogenesis in obesity. These genes show perturbations in DNA methylation and expression profiles in patients with obesity and diabetes. Methylation profiles were able to discriminate OND from OD individuals; DNA methylation is thus a potential biomarker.

DNA Methylation Remodeling after Bariatric Surgery Correlates with Clinical Parameters

“…To delimit DMCs with a correlation between DNA methylation level and BMI, a Pearson's correlation was performed with a bootstrap analysis with the Boot package, to select only robust associations, as previously described. [33,34] The same approach was applied to correlate the methylation levels of the DMCs with the other post-surgical clinical parameters.…”

Epigenetic modifications in obesity‐associated diseases

“…By examining the DNAm profiles of individuals with T2D, researchers have identified novel candidate genes associated with T2D and enhanced comprehension of the disease's pathogenesis 72 . Obesity primarily leads to the development of T2D by inducing IR and disrupting lipid metabolism.…”

EH domain‐containing protein 2 (EHD2): Overview, biological function, and therapeutic potential

“…59 According to Baca et al, obesity is associated with changes in DNA methylation and gene expression specific among different fat tissue depots, including EHD2. 60 At the same time, individuals who are obese show minimal expression of EHD2, and GLUT4 endocytosis into adipocytes increased, 49 suggesting that the regulation of caveolar dynamics by EHD2 may play a role in the development of obesity. 58 During the differentiation process of adipocytes, once triglycerides accumulate, the expression of EHD2 protein is highly upregulated.…”

“…80 Baca et al found that EHD2 is one of the epigenetic genes that exhibit DNA methylation and gene expression abnormalities in obese and type 2 diabetes patients and is significantly correlated with blood glucose and HbA1c levels. 60 In addition, EHD2 can stabilize caveolae on the membrane, while the loss of caveolae leads to lipodystrophic diabetes in humans. 81 In addition, EHD2 has been shown to regulate the trafficking of GLUT4, which is essential for glucose uptake in insulin-sensitive tissues such as skeletal muscle and adipose tissue.…”

“…The dysfunction of EHD2 is involved in the development of insulin resistance and glucose intolerance, both of which are major symptoms of diabetes 80 . Baca et al found that EHD2 is one of the epigenetic genes that exhibit DNA methylation and gene expression abnormalities in obese and type 2 diabetes patients and is significantly correlated with blood glucose and HbA1c levels 60 . In addition, EHD2 can stabilize caveolae on the membrane, while the loss of caveolae leads to lipodystrophic diabetes in humans 81 .…”