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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

Genomic distribution of DMS between obese and never-obese women in relation to CpG content (left) and functional parts of genes (right). The genomic distribution of 5529 DMS between obese and never-obese women (black bars) (FDR 1 %) were compared to all 319,596 analyzed CpG probes (hatched bars). TSS1500; within 1500 basepairs of transcriptional start site (TSS). TSS200; within 200 basepairs of TSS
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Fig2: Genomic distribution of DMS between obese and never-obese women in relation to CpG content (left) and functional parts of genes (right). The genomic distribution of 5529 DMS between obese and never-obese women (black bars) (FDR 1 %) were compared to all 319,596 analyzed CpG probes (hatched bars). TSS1500; within 1500 basepairs of transcriptional start site (TSS). TSS200; within 200 basepairs of TSS

Mentions: Among 319,596 analyzed CpG sites, there were 32,724 DMS in fat cells between obese cases versus never-obese controls according to Limma and applying a FDR <1 % (Additional file 1: Table S1). We focused the subsequent analysis on the 23,576 DMS linked to genes. Global transcriptome analysis identified 3878 differentially expressed genes in WAT between obese cases and never-obese controls applying thresholds FDR 5 % and fold change 20 % (Additional file 1: Table S2); 2546 of these genes were expressed at higher levels in obese women. We did not have enough material to perform transcriptome analysis on isolated fat cells. However, since the expression of genes involved in metabolism often display enriched expression in fat cells as compared to stroma cells, we believe that the WAT transcriptome data provide valid information about differential gene expression of relevance also for fat cells. Next, we compared the 23,576 DMS with the 3878 differentially expressed genes and identified 5529 DMS associated with 2223 differentially expressed genes between obese cases and never-obese controls (Additional file 1: Table S3). The 5529 DMS displayed a median difference in beta value of 0.09 (range 0.01 to 0.40) between the obese cases and never-obese controls. The genomic distribution of the 5529 DMS, as compared to all 319,596 analyzed probes, is shown in Fig. 2 in relation to CpG content and functional parts of genes. DMS were under-represented in CpG islands and over-represented in open sea-regions. DMS were under-represented in promoter regions (TSS1500, TSS200) and over-represented in gene bodies. We related CpG methylation at individual DMS to gene expression (Table 2). DMS with inverse association to gene expression were modestly (58 %) over-represented in the 5′ regions of genes (i.e., TSS1500, TSS200, 5′UTR, and first exon) as compared to DMS with directionally consistent change in DNA methylation and expression comparing obese versus never-obese women. DMS in gene bodies and 3′UTR regions displayed an equal distribution of negative and positive associations between DNA methylation and gene expression.Fig. 2


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)

Genomic distribution of DMS between obese and never-obese women in relation to CpG content (left) and functional parts of genes (right). The genomic distribution of 5529 DMS between obese and never-obese women (black bars) (FDR 1 %) were compared to all 319,596 analyzed CpG probes (hatched bars). TSS1500; within 1500 basepairs of transcriptional start site (TSS). TSS200; within 200 basepairs of TSS
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Genomic distribution of DMS between obese and never-obese women in relation to CpG content (left) and functional parts of genes (right). The genomic distribution of 5529 DMS between obese and never-obese women (black bars) (FDR 1 %) were compared to all 319,596 analyzed CpG probes (hatched bars). TSS1500; within 1500 basepairs of transcriptional start site (TSS). TSS200; within 200 basepairs of TSS
Mentions: Among 319,596 analyzed CpG sites, there were 32,724 DMS in fat cells between obese cases versus never-obese controls according to Limma and applying a FDR <1 % (Additional file 1: Table S1). We focused the subsequent analysis on the 23,576 DMS linked to genes. Global transcriptome analysis identified 3878 differentially expressed genes in WAT between obese cases and never-obese controls applying thresholds FDR 5 % and fold change 20 % (Additional file 1: Table S2); 2546 of these genes were expressed at higher levels in obese women. We did not have enough material to perform transcriptome analysis on isolated fat cells. However, since the expression of genes involved in metabolism often display enriched expression in fat cells as compared to stroma cells, we believe that the WAT transcriptome data provide valid information about differential gene expression of relevance also for fat cells. Next, we compared the 23,576 DMS with the 3878 differentially expressed genes and identified 5529 DMS associated with 2223 differentially expressed genes between obese cases and never-obese controls (Additional file 1: Table S3). The 5529 DMS displayed a median difference in beta value of 0.09 (range 0.01 to 0.40) between the obese cases and never-obese controls. The genomic distribution of the 5529 DMS, as compared to all 319,596 analyzed probes, is shown in Fig. 2 in relation to CpG content and functional parts of genes. DMS were under-represented in CpG islands and over-represented in open sea-regions. DMS were under-represented in promoter regions (TSS1500, TSS200) and over-represented in gene bodies. We related CpG methylation at individual DMS to gene expression (Table 2). DMS with inverse association to gene expression were modestly (58 %) over-represented in the 5′ regions of genes (i.e., TSS1500, TSS200, 5′UTR, and first exon) as compared to DMS with directionally consistent change in DNA methylation and expression comparing obese versus never-obese women. DMS in gene bodies and 3′UTR regions displayed an equal distribution of negative and positive associations between DNA methylation and gene expression.Fig. 2

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