Glucocorticoid receptor gene expression in adipose tissue and associated metabolic risk in black and white South African women

Goedecke, Julia H.; Chorell, Elin; Livingstone, Dawn E W; Stimson, Roland H; Hayes, Philip M.; Adams, Kevin; Dave, Joel A.; Victor, Hendriena; Levitt, Naomi; Kahn, Steven E.; Walker, Brian R.; Olsson, Tommy

doi:10.1038/ijo.2014.94

Cited by 8 publications

(5 citation statements)

References 37 publications

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“…While the magnitude of GR methylation alterations between obese and normal weight women are less pronounced compared to those identified in, for example, various types of malignant disorders [ 30 , 31 ], they are consistent with genome-wide association studies showing subtle changes in GR methylation, including sites within exon 1F, in numerous disorders [ 32 – 34 ]. Furthermore, GR mRNA expression was downregulated in GSAT from our obese study population [ 19 ], and although its expression did not correlate with methylation levels (data not shown), it is now widely accepted that DNA methylation marks are functionally complex and may orchestrate other important regulatory events, including alternative splicing and even the promotion of gene transcription [ 8 ]. However, we cannot rule out the possibility of other genetic/epigenetic mechanisms underlying GR regulation in this study, such as the presence of SNPs or inhibition by non-coding RNAs and/or histone modifications [ 22 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

et al. 2020

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Background Disruption of the hypothalamic–pituitary–adrenal (HPA) axis, a neuroendocrine system associated with the stress response, has been hypothesized to contribute to obesity development. This may be mediated through epigenetic modulation of HPA axis-regulatory genes in response to metabolic stressors. The aim of this study was to investigate adipose tissue depot-specific DNA methylation differences in the glucocorticoid receptor (GR) and its co-chaperone, FK506-binding protein 51 kDa (FKBP5), both key modulators of the HPA axis. Methods Abdominal subcutaneous adipose tissue (ASAT) and gluteal subcutaneous adipose tissue (GSAT) biopsies were obtained from a sample of 27 obese and 27 normal weight urban-dwelling South African women. DNA methylation and gene expression were measured by pyrosequencing and quantitative real-time PCR, respectively. Spearman’s correlation coefficients, orthogonal partial least-squares discriminant analysis and multivariable linear regression were performed to evaluate the associations between DNA methylation, messenger RNA (mRNA) expression and key indices of obesity and metabolic dysfunction. Results Two CpG dinucleotides within intron 7 of FKBP5 were hypermethylated in both ASAT and GSAT in obese compared to normal weight women, while no differences in GR methylation were observed. Higher percentage methylation of the two FKBP5 CpG sites correlated with adiposity (body mass index and waist circumference), insulin resistance (homeostasis model for insulin resistance, fasting insulin and plasma adipokines) and systemic inflammation (c-reactive protein) in both adipose depots. GR and FKBP5 mRNA levels were lower in GSAT, but not ASAT, of obese compared to normal weight women. Moreover, FKBP5 mRNA levels were inversely correlated with DNA methylation and positively associated with adiposity, metabolic and inflammatory parameters. Conclusions These findings associate dysregulated FKBP5 methylation and mRNA expression with obesity and insulin resistance in South African women. Additional studies are required to assess the longitudinal association of FKBP5 with obesity and associated co-morbidities in large population-based samples. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

et al. 2020

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“…Further, we showed that lower accumulation of VAT relative to SAT in ↑ hyperinsulinaemia [5,[7][8][9][10][11][12]16] ↑ insulin response/secretion [5,[7][8][9][10][11][12]16] ↓ hepatic insulin clearance [7,12,16,17] ↔ extra-hepatic insulin clearance [17] ↑ hepatic insulin sensitivity [35,36] ↓ gluconeogenesis [36] ↑ higher; ↓ lower, ↔ similar. black compared to white South African women may be related to their lower glucocorticoid receptor alpha expression in abdominal and gluteal SAT depots [53].…”

Section: Obesity and Body Fat Distributionmentioning

confidence: 99%

“…Although ER expression in abdominal SAT did not differ by ethnicity, black African women had higher gluteal ERα and lower ERβ expression than their white counterparts, which correlated with lower central fat mass and greater gynoid fat mass [52]. Further, we showed that lower accumulation of VAT relative to SAT in black compared to white South African women may be related to their lower glucocorticoid receptor alpha expression in abdominal and gluteal SAT depots [53].…”

Section: Determinants Of Insulin Sensitivity Secretion and Clearancementioning

confidence: 99%

Pathogenesis of type 2 diabetes risk in black Africans: a South African perspective

Goedecke

Olsson

2020

J Intern Med

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The prevalence of type 2 diabetes (T2D) is higher in black Africans than their European counterparts. This review summarizes the research exploring the pathogenesis of T2D in populations of African ancestry compared to white Europeans and shows that the pathogenesis differs by ethnicity. Black Africans present with a phenotype of low insulin sensitivity and hyperinsulinaemia as a result of increased insulin secretion and reduced hepatic insulin clearance. Whether hyperinsulinaemia precedes insulin resistance or is merely a compensatory mechanism is yet to be determined. Black Africans have lower visceral adipose tissue and ectopic fat deposition and greater peripheral (gluteo‐femoral) fat deposition than their European counterparts. This suggests that black Africans are more sensitive to the effects of ectopic fat deposition, or alternatively, that ectopic fat is not an important mediator of T2D in black Africans. Importantly, ethnic disparities in T2D risk factors may be confounded by differences in sociocultural and lifestyle factors. Future longitudinal and dietary intervention studies, in combination with genetic analyses, are needed for a better understanding of the pathophysiology of T2D in black Africans. This will be key for effective prevention and management strategies.

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“…Although the mechanisms underlying these ethnic differences are not yet known, a recent study suggested that glucocorticoids may be involved (16). Goedecke et al, (16) reported that black South African women demonstrated lower gene expression of the glucocorticoid receptor (GR) in subcutaneous adipose tissue (SAT) than women of European ancestry. The lower GR expression in these African women was associated with less VAT, higher SAT inflammation, and whole-body lower insulin sensitivity.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies have shown that in urban settings Africans have a higher prevalence of obesity and insulin resistance, yet have less visceral adipose tissue (VAT) than Europeans ( 13 , 14 , 15 ). Although the mechanisms underlying these ethnic differences are not yet known, a recent study suggested that glucocorticoids may be involved ( 16 ). Goedecke et al ( 16 ) reported that black South African women demonstrated lower gene expression of the glucocorticoid receptor (GR) in s.c. adipose tissue (SAT) than women of European ancestry.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoids associate with cardiometabolic risk factors in black South Africans

Dlamini

Lombard

Micklesfield

et al. 2021

Endocrine Connections

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Circulating glucocorticoids are associated with the metabolic syndrome and related cardiometabolic risk factors in non-Africans. This study investigated these associations in Africans, whose metabolic phenotype reportedly differs from Europeans. Measures of adiposity, blood pressure, glycaemia, insulin resistance, and lipid profile, were measured in 316 African men and 788 African women living in Soweto, Johannesburg. The 2009 harmonized criteria were used to define the metabolic syndrome. Serum glucocorticoids were measured using liquid chromatography-mass spectrometry. Cortisol was associated with greater odds of presenting with the metabolic syndrome (odds ratio (95% confidence interval, 95%CI) =1.50 [1.04, 2.17] and higher systolic (beta coefficient, β (95%CI) =0.04 [0.01, 0.08]) and diastolic (0.05 [0.02, 0.09]) blood pressure, but higher HDL (0.10 [0.02, 0.19]) and lower LDL (-0.14 [-0.24, -0.03]) cholesterol concentrations, in the combined sample of men and women. In contrast, corticosterone was only associated with higher insulin sensitivity (Matsuda index; 0.22 [0.03, 0.41]), but this was not independent of BMI. Sex-specific associations were observed, such that both cortisol and corticosterone were associated with higher fasting glucose (standardized β (95%CI): 0.24 [0.12, 0.36] for cortisol; and 0.12 [0.01, 0.23] for corticosterone) and HbA1c (0.13 [0.01, 0.25] for cortisol; and 0.12 [0.01, 0.24] for corticosterone) in men only, but lower HbA1c (0.10 [ -0.20, -0.01] for cortisol; and -0.09 [-0.18, -0.03] for corticosterone) in women only. Our study reports for the first time that associations between circulating glucocorticoid concentrations and key cardiometabolic risk factors exhibit both glucocorticoid- and sex-specificity in Africans.

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Glucocorticoid receptor gene expression in adipose tissue and associated metabolic risk in black and white South African women

Abstract: In black SA women, downregulation of GRα mRNA levels with obesity and reduced insulin sensitivity, possibly via increased SAT inflammation, is associated with reduced VAT accumulation.

Cited by 8 publications

References 37 publications

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

Pathogenesis of type 2 diabetes risk in black Africans: a South African perspective

Glucocorticoids associate with cardiometabolic risk factors in black South Africans

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