Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

Rönn, Tina; Volkov, Petr; Gillberg, Linn; Kokosar, Milana; Perfilyev, Alexander; Jacobsen, Anna Louisa; Jørgensen, Steffen; Brøns, Charlotte; Jansson, Per‐Anders; Eriksson, Karl-Fredrik; Pedersen, Oluf; Hansen, Torben; Groop, Leif; Stener-Victorin, Elisabet; Vaag, Allan; Nilsson, Erika; Ling, Charlotte

doi:10.1093/hmg/ddv124

Cited by 191 publications

(267 citation statements)

References 90 publications

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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 Bloosupporting

confidence: 61%

“…As previous studies have linked adipose tissue DNA methylation to both BMI and type 2 diabetes [8][9][10], it is reasonable to assume an association also with insulin resistance. 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.…”

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

confidence: 96%

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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 Bloosupporting

confidence: 61%

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

confidence: 96%

Epigenetic markers to further understand insulin resistance

Ling

Rönn

2016

Diabetologia

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“…In addition, changes in cell type composition could be responsible for some of the changes in HFO-induced gene expression. However, when we investigated 24 cell-typespecific markers for adipocytes, pre-adipocytes, brown adipocytes, macrophages, cytokines and inflammation [12], only LEP, TNF (cytokines) and CIDEA (brown adipocyte marker) were differentially expressed after HFO. These data suggest that 5 days HFO does not alter the cellular composition of SAT.…”

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%

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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“…This may be due to the facts that environmental factors (including nutrition) across individuals are very heterogeneous, and target tissues (such as adipose tissue) are not easy to access. Furthermore, recent data by Rönn et al suggests that the human DNA methylome in SAT changes considerably with age [185]. They also found BMI exerts effects on the degree of DNA methylation in human adipose tissue, proposing that obesity can mediate some of its effect through changes in the epigenome.…”

Section: Epigeneticsmentioning

confidence: 96%

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

Schleinitz¹

2016

Rev Diabet Stud

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■ AbstractAdipose tissue secretes an abundance of proteins. Some of these proteins are known as adipokines and adipose-derived hormones which have been linked with metabolic disorders, including type 2 diabetes, and even with cancer. Variance in serum adipokine concentration is often closely associated with an increase (obesity) or decrease (lipodystrophy) in fat tissue mass, and it is affected by age, gender, and localization of the adipose tissue. However, there may be genetic variants which, in consequence, influence the serum concentration of a certain adipokine, and thereby promote metabolic disturbances or, with regard to the "protective" allele, exert beneficial effects. This review focuses on the genetic determination of serum levels of the following adipokines: adiponectin, chemerin, leptin, progranulin, resistin, retinol binding protein 4, vaspin, adipsin, apelin, and omentin. The article reports on the latest findings from genome-wide association studies (GWAS) and candidate gene studies, showing variants located in/nearby the adipokine genes and other (non-receptor) genes. An extra chapter highlights adipokine-receptor variants. Epigenetic studies on adipokines are also addressed.

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Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

Cited by 191 publications

References 90 publications

Epigenetic markers to further understand insulin resistance

Epigenetic markers to further understand insulin resistance

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

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

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