Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes

Nilsson, Erika; Jansson, Per Anders; Perfilyev, Alexander; Volkov, Petr; Pedersen, Maria; Svensson, Maria; Poulsen, Pernille; Ribel‐Madsen, Rasmus; Pedersen, Nancy L.; Almgren, Peter; Fadista, João; Rönn, Tina; Pedersen, Bente Klarlund; Schéele, Camilla; Vaag, Allan; Ling, Charlotte

doi:10.2337/db13-1459

Cited by 344 publications

(331 citation statements)

References 51 publications

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“…It should be noted that we previously identified extensive epigenetic alterations in human adipose tissue from other cohorts of a similar size to the one included in this study [9,11]. These studies together with our post hoc power calculation suggest an appropriate statistical power in the present study.…”

Section: Discussionmentioning

confidence: 72%

“…Interestingly, we recently found that ELOVL6, FADS1, FADS2 and GYS2 are among the most strongly downregulated genes in SAT from monozygotic twins discordant for type 2 diabetes [9]. In addition, the gene sets that were most significantly upregulated by HFO in this study (oxidative phosphorylation, citrate cycle and pyruvate metabolism) were significantly downregulated in SAT from diabetic twins [9]. A disturbed adipocyte metabolism has been suggested to shift lipid storage into alternative tissues, such as skeletal muscle, the liver and the pancreas, resulting in insulin resistance [36].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, young, healthy LBW men develop more severe peripheral insulin resistance when exposed to 5 days of high-fat overfeeding (HFO) compared with men with a normal birthweight (NBW) [1]. Lifestyle-related factors may alter epigenetic and transcriptional patterns [5][6][7][8][9][10][11][12], and thereby affect the risk of metabolic diseases. Indeed, we observed widespread DNA methylation changes in skeletal muscle from healthy young men after 5 days of HFO [7]; in contrast, there were no significant epigenetic changes in matched LBW men after HFO [13].…”

Section: Introductionmentioning

confidence: 99%

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Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

et al. 2016

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Aims/hypothesis Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. Methods mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. Results We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes-and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. Conclusions/interpretation Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

et al. 2016

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“…A recent study on adipose tissue from monozygotic twins discordant for T2DM (diabetics vs. non-diabetics) reported increased expression of inflammatory genes, such as secreted phosphoprotein (SPP)1 (also known as osteopontin, OPN), chemokine (C-C motif) ligand (CCL)18 and IL1RN, in association with variations of global and localized DNA methylation. 43 Moreover, the methylation of 7 CpGs in the promoter of the gene coding for the inflammatory molecule Toll-like receptor (TLR)-2 was significantly lower in T2DM patients compared with controls, and this difference was associated with marked variation in the composition of gut microbiota. 44 Inflammation has also been recognized as the pathogenic link between obesity and T2DM.…”

Section: B-cell Development and Functionmentioning

confidence: 99%

“…1). 43 Epigenetics could be extremely important also in the inflammatory response of the hypertrophic adipose tissue in obese people. Remarkably, lean and obese individuals present differentially expressed miRNAs in their adipose tissue.…”

Section: B-cell Development and Functionmentioning

confidence: 99%

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

et al. 2017

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Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling b-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects. We discuss the effect of epigenetics on b-cell regeneration for cell replacement therapy, the emerging bioinformatics approaches for analyzing the epigenetic contribution to type 2 diabetes mellitus (T2DM), the epigenetic core of the transgenerational inheritance hypothesis in T2DM, and the epigenetic clinical trials on T2DM. Therefore, prevention or reversion of the epigenetic changes occurring during T2DM development may reduce the individual and societal burden of the disease.

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Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis

et al. 2018

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Aminoacyl‐tRNA synthetases are ubiquitous enzymes, which universally charge tRNAs with their cognate amino acids for use in cytosolic or organellar translation. In humans, mutations in mitochondrial tRNA synthetases have been linked to different tissue‐specific pathologies. Mutations in the KARS gene, which encodes both the cytosolic and mitochondrial isoform of lysyl‐tRNA synthetase, cause predominantly neurological diseases that often involve deafness, but have also been linked to cardiomyopathy, developmental delay, and lactic acidosis. Using whole exome sequencing, we identified two compound heterozygous mutations, NM_001130089.1:c.683C>T p.(Pro228Leu) and NM_001130089.1:c.1438del p.(Leu480TrpfsX3), in a patient presenting with sensorineural deafness, developmental delay, hypotonia, and lactic acidosis. Nonsense‐mediated mRNA decay eliminated the truncated mRNA transcript, rendering the patient hemizygous for the missense mutation. The c.683C>T mutation was previously described, but its pathogenicity remained unexamined. Molecular characterization of patient fibroblasts revealed a multiple oxidative phosphorylation deficiency due to impaired mitochondrial translation, but no evidence of inhibition of cytosolic translation. Reintroduction of wild‐type mitochondrial KARS, but not the cytosolic isoform, rescued this phenotype confirming the disease‐causing nature of p.(Pro228Leu) exchange and demonstrating the mitochondrial etiology of the disease. We propose that mitochondrial translation deficiency is the probable disease culprit in this and possibly other patients with mutations in KARS.

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Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes

Cited by 344 publications

References 51 publications

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis

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