Abstract
BackgroundThe current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. Monozygotic (MZ) twin pairs showing discordance for obesity suggest that epigenetic influences represent one such mechanism. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index (BMI; average within-pair BMI difference: 5.4 ± 2.0 kg/m2).ResultsThere were no differentially methylated cytosine-guanine (CpG) sites between the co-twins discordant for BMI. However, stratification of the twin pairs based on the level of liver fat accumulation revealed two epigenetically highly different groups. Significant DNA methylation differences (n = 1,236 CpG sites (CpGs)) between the co-twins were only observed if the heavier co-twins had excessive liver fat (n = 13 twin pairs). This unhealthy pattern of obesity was coupled with insulin resistance and low-grade inflammation. The differentially methylated CpGs included 23 genes known to be associated with obesity, liver fat, type 2 diabetes mellitus (T2DM) and metabolic syndrome, and potential novel metabolic genes. Differentially methylated CpG sites were overrepresented at promoters, insulators, and heterochromatic and repressed regions. Based on predictions by overlapping histone marks, repressed and weakly transcribed sites were significantly more often hypomethylated, whereas sites with strong enhancers and active promoters were hypermethylated. Further, significant clustering of differentially methylated genes in vitamin, amino acid, fatty acid, sulfur, and renin-angiotensin metabolism pathways was observed.ConclusionsThe methylome in leukocytes is altered in obesity associated with metabolic disturbances, and our findings indicate several novel candidate genes and pathways in obesity and obesity-related complications.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0073-5) contains supplementary material, which is available to authorized users.
Highlights
The current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans
Except for high-density lipoprotein (HDL), were observed in the group where the heavier co-twins had normal levels of liver fat. Based on these within-pair differences in the metabolic profiles, we hereafter refer to the pairs discordant for body mass index (BMI) but concordant for liver fat as the normal liver fat group and the pairs discordant for both BMI and liver fat as the elevated liver fat group
We show that DNA methylation profiles in blood leukocytes differ between BMI-discordant MZ cotwins only when high BMI is coupled with elevated liver fat and preclinical state metabolic disturbances
Summary
The current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index (BMI; average within-pair BMI difference: 5.4 ± 2.0 kg/m2). 30% of obese individuals appear metabolically healthy [1]. These individuals are insulin sensitive and have normal liver fat and visceral fat content, and their adipose tissue remains free of inflammation and mitochondrial dysfunction [1,2]. The development of high levels of liver fat predicts other metabolic complications, and nonalcoholic fatty liver disease is closely associated with obesity in many, but not all obese
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