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Circulating cortisol-associated signature of glucocorticoid-related gene expression in subcutaneous fat of obese subjects.

ABSTRACT: OBJECTIVE:Serum cortisol concentrations fluctuate in a circadian fashion, and glucocorticoids exert strong effects on adipose tissue and induce obesity through the glucocorticoid receptor. DESIGN AND METHODS:To examine the impact of physiologic levels of circulating cortisol on subcutaneous adipose tissue, 25 overweight and obese subjects were employed, and their serum levels of morning (AM) and evening (PM) cortisol, AM/PM cortisol ratios, and 24-h urinary-free cortisol (UFC) were compared with their clinical parameters, serum cytokine levels, and mRNA expression of 93 receptor action-regulating and 93 glucocorticoid-responsive genes in abdominal subcutaneous fat. RESULTS AND CONCLUSIONS:AM cortisol levels did not correlate with mRNA expression of the all genes examined, whereas PM cortisol levels, AM/PM cortisol ratios, and 24-h UFC were associated with distinct sets of these genes. Body mass index did not significantly correlate with the four cortisol parameters employed. These results suggest that physiologic levels of AM serum cortisol do not solely represent biological effects of circulating cortisol on the expression of glucocorticoid-related genes in subcutaneous adipose tissue, whereas PM levels, amplitude, and net amounts of the diurnally fluctuating serum cortisol have distinct effects. Through the genes identified in this study, glucocorticoids appear to influence intermediary metabolism, energy balance, inflammation, and local circadian rythmicity in subcutaneous fat. Our results may also explain in part the development of metabolic abnormality and obesity in subjects under stress or patients with melancholic/atypical depression who demonstrate elevated levels of PM serum cortisol.

SUBMITTER: Pavlatou MG

PROVIDER: S-EPMC4199221 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Circulating cortisol-associated signature of glucocorticoid-related gene expression in subcutaneous fat of obese subjects.

Pavlatou Maria G MG Vickers Kasey C KC Varma Sudhir S Malek Rana R Sampson Maureen M Remaley Alan T AT Gold Philip W PW Skarulis Monica C MC Kino Tomoshige T

Obesity (Silver Spring, Md.) 20130501 5

<h4>Objective</h4>Serum cortisol concentrations fluctuate in a circadian fashion, and glucocorticoids exert strong effects on adipose tissue and induce obesity through the glucocorticoid receptor.<h4>Design and methods</h4>To examine the impact of physiologic levels of circulating cortisol on subcutaneous adipose tissue, 25 overweight and obese subjects were employed, and their serum levels of morning (AM) and evening (PM) cortisol, AM/PM cortisol ratios, and 24-h urinary-free cortisol (UFC) wer ...[more]

PMID: 23784897

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Project description: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.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.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.

Project description:Background and aims:Subcutaneous fat mass is negatively correlated with atherogenic risk factors, but its putative benefits remain controversial. We hypothesized that genetic variants that influence subcutaneous fat mass would modulate lipid and glucose metabolism and have interactions with lifestyles in Korean middle-aged adults with high visceral fat. Materials and methods:Subcutaneous fat mass was categorized by dividing the average of subscapular skin-fold thickness by BMI and its cutoff point was 1.2. Waist circumferences were used for representing visceral fat mass with Asian cutoff points. GWAS of subjects aged 40-65?years with high visceral fat (n?=?3303) were conducted and the best gene-gene interactions from the genetic variants related to subcutaneous fat were selected and explored using the generalized multifactor dimensionality reduction. Genetic risk scores (GRS) were calculated by weighted GRS that was divided into low, medium and high groups. Results:Subjects with high subcutaneous fat did not have dyslipidemia compared with those with low subcutaneous fat, although both subject groups had similar amounts of total fat. The best model to influence subcutaneous fat included IL17A_rs4711998, ADCY2_rs326149, ESRRG_rs4846514, CYFIP2_rs733730, TCF7L2_rs7917983, ZNF766_rs41497444 and TGFBR3_rs7526590. The odds ratio (OR) for increasing subcutaneous fat was higher by 2.232 folds in the high-GRS group, after adjusting for covariates. However, total and LDL cholesterol, triglyceride and C-reactive protein concentrations in the circulation were not associated with GRS. Subjects with high-GRS had higher serum HDL cholesterol levels than those with low-GRS. Physical activity and GRS had an interaction with subcutaneous fat. In subjects with low physical activity, the odds ratio for high subcutaneous fat increased by 2.232, but subcutaneous fat deposition was not affected in the high-GRS group with high physical activity. Conclusion:Obese adults with high-GRS had more subcutaneous fat, but they did not show more dyslipidemia and inflammation compared to low-GRS. High physical activity prevented subcutaneous fat deposition in subjects with high GRS for subcutaneous fat.

Dataset Information

Circulating cortisol-associated signature of glucocorticoid-related gene expression in subcutaneous fat of obese subjects.

Publications

Circulating cortisol-associated signature of glucocorticoid-related gene expression in subcutaneous fat of obese subjects.

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