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

Gillberg, Linn; Perfilyev, Alexander; Brøns, Charlotte; Thomasen, Martin; Grunnet, Louise Groth; Volkov, Petr; Rosqvist, Fredrik; Iggman, David; Dahlman, Ingrid; Risérus, Ulf; Rönn, Tina; Nilsson, Erika; Vaag, Allan; Ling, Charlotte

doi:10.1007/s00125-015-3852-9

Cited by 66 publications

(53 citation statements)

References 48 publications

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“…The involvement of epigenetic factors in insulin resistance is also supported by the theory of a metabolic memory, linking an impaired intrauterine environment to increased risk for insulin resistance later in life [5].…”

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

confidence: 94%

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%

Epigenetic markers to further understand insulin resistance

Ling

Rönn

2016

Diabetologia

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“…1,[5][6][7] Therefore, epigenetic modifications, either inherited or induced by lifestyles, 8,9 may play a key role in the pathogenesis of the disease. To some extent, the epigenetic mechanisms resulting in aberrant histone modifications, differences in DNA methylation, and dysregulation of microRNAs are the ones that have been related to NAFLD and its transition to more advanced stages.…”

Section: Introductionmentioning

confidence: 99%

Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

et al. 2017

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Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 § 7.7 years, BMI: 43 § 5.7 kg/m 2 , type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q < 0.001), independently of T2D, age, sex, and BMI. Focusing on the top-ranking 30 and another 37 CpG sites mapped to genes enriched in pathways of metabolism (q D 0.0036) and cancer (q D 0.0001) all together, 59 NASH-associated CpG sites correlated with fasting insulin levels independently of age, fasting glucose, or T2D. From these, we identified 30 correlations between DNA methylation and mRNA expression, for example LDHB (r D ¡0.45, P D 0.003). We demonstrated that NASH, more than simple steatosis, associates with differential DNA methylation in the human liver. These epigenetic alterations in NASH are linked with insulin metabolism.

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“…The literature investigating effects of nutritional challenges on DNA methylation in humans is limited and includes studies addressing effects of high-calorie diets [6–9]. We have previously found that LBW subjects, when undergoing a high-fat feeding, exhibit less changeability in muscle tissue DNA methylation than matched NBW controls [33].…”

Section: Discussionmentioning

confidence: 99%

“…However, today we experience an increasing understanding of environmental regulation of DNA methylation in adult life, and recent studies have shown that ageing [1–3], exercise [4, 5], and dietary factors [6–9] can alter site-specific DNA methylation in humans, across different tissues. Epigenetic modifications have further been associated with differential gene expression and altered metabolism in key diabetic tissues, including adipose tissue [4, 10–12].…”

Section: Introductionmentioning

confidence: 99%

“…Being born with low birth weight (LBW) has been confirmed in several human studies to be associated with increased risk of developing insulin resistance and T2D in adult life [22–24]. In this regard, several studies have reported alterations of epigenetic patterns and plasticity in human tissues that are relevant to metabolic diseases in subjects born at term with a LBW compared to normal birth weight (NBW) subjects [6, 8, 9, 25]. …”

Section: Introductionmentioning

confidence: 99%

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36 h fasting of young men influences adipose tissue DNA methylation of LEP and ADIPOQ in a birth weight-dependent manner

et al. 2017

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BackgroundSubjects born with low birth weight (LBW) display a more energy-conserving response to fasting compared with normal birth weight (NBW) subjects. However, the molecular mechanisms explaining these metabolic differences remain unknown. Environmental influences may dynamically affect epigenetic marks, also in postnatal life. Here, we aimed to study the effects of short-term fasting on leptin (LEP) and adiponectin (ADIPOQ) DNA methylation and gene expression in subcutaneous adipose tissue (SAT) from subjects with LBW and NBW.MethodsTwenty-one young LBW men and 18 matched NBW controls were studied during 36 h fasting. Eight subjects from each group completed a control study (overnight fast). We analyzed SAT LEP and ADIPOQ methylation (Epityper MassARRAY), gene expression (q-PCR), and adipokine plasma levels.ResultsAfter overnight fast (control study), LEP and ADIPOQ DNA methylation levels were higher in LBW compared to those in NBW subjects (p ≤ 0.03) and increased with 36 h fasting in NBW subjects only (p ≤ 0.06). Both LEP and ADIPOQ methylation levels were positively associated with total body fat percentage (p ≤ 0.05). Plasma leptin levels were higher in LBW versus NBW subjects after overnight fasting (p = 0.04) and decreased more than threefold in both groups after 36 h fasting (p ≤ 0.0001).ConclusionsThis is the first study to demonstrate that fasting induces changes in DNA methylation. This was shown in LEP and ADIPOQ promoters in SAT among NBW but not LBW subjects. The altered epigenetic flexibility in LBW subjects might contribute to their differential response to fasting, adipokine levels, and increased risk of metabolic disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0340-8) contains supplementary material, which is available to authorized users.

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

Cited by 66 publications

References 48 publications

Epigenetic markers to further understand insulin resistance

Epigenetic markers to further understand insulin resistance

Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

36 h fasting of young men influences adipose tissue DNA methylation of LEP and ADIPOQ in a birth weight-dependent manner

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