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The epigenetic signature of subcutaneous fat cells is linked to altered expression of genes implicated in lipid metabolism in obese women.

Arner P, Sinha I, Thorell A, Rydén M, Dahlman-Wright K, Dahlman I - Clin Epigenetics (2015)

Bottom Line: Obesity is associated with changes in fat cell gene expression and metabolism.The 2223 differentially expressed genes with DMS were over-represented in key fat cell pathways: 31 of 130 (25 %) genes linked to "adipogenesis" (adjusted P = 1.66 × 10(-11)), 31 of 163 (19 %) genes linked to "insulin signaling" (adjusted P = 1.91 × 10(-9)), and 18 of 67 (27 %) of genes linked to "lipolysis" (P = 6.1 × 10(-5)).These alterations may contribute to obesity-associated metabolic disturbances such as insulin resistance in women.

View Article: PubMed Central - PubMed

Affiliation: Lipid laboratory, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, S-141 86 Sweden.

ABSTRACT

Background: Obesity is associated with changes in fat cell gene expression and metabolism. What drives these changes is not well understood. We aimed to explore fat cell epigenetics, i.e., DNA methylation, as one mediator of gene regulation, in obese women. The global DNA methylome for abdominal subcutaneous fat cells was compared between 15 obese case (BMI 41.4 ± 4.4 kg/m(2), mean ± SD) and 14 never-obese control women (BMI 25.2 ± 2.5 kg/m(2)). Global array-based transcriptome analysis was analyzed for subcutaneous white adipose tissue (WAT) from 11 obese and 9 never-obese women. Limma was used for statistical analysis.

Results: We identified 5529 differentially methylated DNA sites (DMS) for 2223 differentially expressed genes between obese cases and never-obese controls (false discovery rate <5 %). The 5529 DMS displayed a median difference in beta value of 0.09 (range 0.01 to 0.40) between groups. DMS were under-represented in CpG islands and in promoter regions, and over-represented in open sea-regions and gene bodies. The 2223 differentially expressed genes with DMS were over-represented in key fat cell pathways: 31 of 130 (25 %) genes linked to "adipogenesis" (adjusted P = 1.66 × 10(-11)), 31 of 163 (19 %) genes linked to "insulin signaling" (adjusted P = 1.91 × 10(-9)), and 18 of 67 (27 %) of genes linked to "lipolysis" (P = 6.1 × 10(-5)). In most cases, gene expression and DMS displayed reciprocal changes in obese women. Furthermore, among 99 candidate genes in genetic loci associated with body fat distribution in genome-wide association studies (GWAS); 22 genes displayed differential expression accompanied by DMS in obese versus never-obese women (P = 0.0002), supporting the notion that a significant proportion of gene loci linked to fat distribution are epigenetically regulated.

Conclusions: Subcutaneous WAT from obese women is characterized by congruent changes in DNA methylation and expression of genes linked to generation, distribution, and metabolic function of fat cells. These alterations may contribute to obesity-associated metabolic disturbances such as insulin resistance in women.

No MeSH data available.


Related in: MedlinePlus

DNA methylation landscape in obese cases versus never-obese control women. After filtering 319,596 CpG probes were mapped to genome regions based on Illumina annotation. We calculated the average level of DNA methylation within the obese (black bars) and never-obese (hatched bars) groups stratified on genome region in relation to CpG content (left), and functional gene regions (right). TSS1500; within 1500 basepairs of transcriptional start site (TSS). TSS200; within 200 basepairs of TSS. *P < 0.05; **P < 0.01
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Fig1: DNA methylation landscape in obese cases versus never-obese control women. After filtering 319,596 CpG probes were mapped to genome regions based on Illumina annotation. We calculated the average level of DNA methylation within the obese (black bars) and never-obese (hatched bars) groups stratified on genome region in relation to CpG content (left), and functional gene regions (right). TSS1500; within 1500 basepairs of transcriptional start site (TSS). TSS200; within 200 basepairs of TSS. *P < 0.05; **P < 0.01

Mentions: The average degree of DNA methylation, i.e., the average beta value for the 319,596 analyzed probes, was higher in fat cells from obese cases (0.425 ± 0.366, mean ± SD) as compared to never-obese controls (0.420 ± 0.375) (P = 1.3 × 10−7). The average level of DNA methylation stratified by genome region in relation to CpG content and functional parts of genes is shown in Fig. 1. The average DNA methylation of CpG sites located in open seas, CpG islands, and surrounding shore regions was significantly higher in obese as compared to never-obese women whereas no significant difference was observed in shelf regions. The average DNA methylation of CpG sites located in 5′ regions of genes and in gene bodies was significantly higher in obese cases as compared to never-obese controls, whereas there was no significant difference in the 1st exons and 3′UTR regions. The mean within-region absolute difference in DNA methylation between groups was small, in all cases less than 1 %.Fig. 1


The epigenetic signature of subcutaneous fat cells is linked to altered expression of genes implicated in lipid metabolism in obese women.

Arner P, Sinha I, Thorell A, Rydén M, Dahlman-Wright K, Dahlman I - Clin Epigenetics (2015)

DNA methylation landscape in obese cases versus never-obese control women. After filtering 319,596 CpG probes were mapped to genome regions based on Illumina annotation. We calculated the average level of DNA methylation within the obese (black bars) and never-obese (hatched bars) groups stratified on genome region in relation to CpG content (left), and functional gene regions (right). TSS1500; within 1500 basepairs of transcriptional start site (TSS). TSS200; within 200 basepairs of TSS. *P < 0.05; **P < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4562340&req=5

Fig1: DNA methylation landscape in obese cases versus never-obese control women. After filtering 319,596 CpG probes were mapped to genome regions based on Illumina annotation. We calculated the average level of DNA methylation within the obese (black bars) and never-obese (hatched bars) groups stratified on genome region in relation to CpG content (left), and functional gene regions (right). TSS1500; within 1500 basepairs of transcriptional start site (TSS). TSS200; within 200 basepairs of TSS. *P < 0.05; **P < 0.01
Mentions: The average degree of DNA methylation, i.e., the average beta value for the 319,596 analyzed probes, was higher in fat cells from obese cases (0.425 ± 0.366, mean ± SD) as compared to never-obese controls (0.420 ± 0.375) (P = 1.3 × 10−7). The average level of DNA methylation stratified by genome region in relation to CpG content and functional parts of genes is shown in Fig. 1. The average DNA methylation of CpG sites located in open seas, CpG islands, and surrounding shore regions was significantly higher in obese as compared to never-obese women whereas no significant difference was observed in shelf regions. The average DNA methylation of CpG sites located in 5′ regions of genes and in gene bodies was significantly higher in obese cases as compared to never-obese controls, whereas there was no significant difference in the 1st exons and 3′UTR regions. The mean within-region absolute difference in DNA methylation between groups was small, in all cases less than 1 %.Fig. 1

Bottom Line: Obesity is associated with changes in fat cell gene expression and metabolism.The 2223 differentially expressed genes with DMS were over-represented in key fat cell pathways: 31 of 130 (25 %) genes linked to "adipogenesis" (adjusted P = 1.66 × 10(-11)), 31 of 163 (19 %) genes linked to "insulin signaling" (adjusted P = 1.91 × 10(-9)), and 18 of 67 (27 %) of genes linked to "lipolysis" (P = 6.1 × 10(-5)).These alterations may contribute to obesity-associated metabolic disturbances such as insulin resistance in women.

View Article: PubMed Central - PubMed

Affiliation: Lipid laboratory, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, S-141 86 Sweden.

ABSTRACT

Background: Obesity is associated with changes in fat cell gene expression and metabolism. What drives these changes is not well understood. We aimed to explore fat cell epigenetics, i.e., DNA methylation, as one mediator of gene regulation, in obese women. The global DNA methylome for abdominal subcutaneous fat cells was compared between 15 obese case (BMI 41.4 ± 4.4 kg/m(2), mean ± SD) and 14 never-obese control women (BMI 25.2 ± 2.5 kg/m(2)). Global array-based transcriptome analysis was analyzed for subcutaneous white adipose tissue (WAT) from 11 obese and 9 never-obese women. Limma was used for statistical analysis.

Results: We identified 5529 differentially methylated DNA sites (DMS) for 2223 differentially expressed genes between obese cases and never-obese controls (false discovery rate <5 %). The 5529 DMS displayed a median difference in beta value of 0.09 (range 0.01 to 0.40) between groups. DMS were under-represented in CpG islands and in promoter regions, and over-represented in open sea-regions and gene bodies. The 2223 differentially expressed genes with DMS were over-represented in key fat cell pathways: 31 of 130 (25 %) genes linked to "adipogenesis" (adjusted P = 1.66 × 10(-11)), 31 of 163 (19 %) genes linked to "insulin signaling" (adjusted P = 1.91 × 10(-9)), and 18 of 67 (27 %) of genes linked to "lipolysis" (P = 6.1 × 10(-5)). In most cases, gene expression and DMS displayed reciprocal changes in obese women. Furthermore, among 99 candidate genes in genetic loci associated with body fat distribution in genome-wide association studies (GWAS); 22 genes displayed differential expression accompanied by DMS in obese versus never-obese women (P = 0.0002), supporting the notion that a significant proportion of gene loci linked to fat distribution are epigenetically regulated.

Conclusions: Subcutaneous WAT from obese women is characterized by congruent changes in DNA methylation and expression of genes linked to generation, distribution, and metabolic function of fat cells. These alterations may contribute to obesity-associated metabolic disturbances such as insulin resistance in women.

No MeSH data available.


Related in: MedlinePlus