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

Clinical Epigenetics

Stephanie Dias¹  Johan Louw²  Tarryn Willmer³  Carmen Pheiffer³  Julia H. Goedecke⁴ 

[1] Biomedical Research and Innovation Platform, South African Medical Research Council, 7505, Tygerberg, South Africa;Biomedical Research and Innovation Platform, South African Medical Research Council, 7505, Tygerberg, South Africa;Department of Biochemistry and Microbiology, University of Zululand, 3886, Kwa-Dlangezwa, South Africa;Biomedical Research and Innovation Platform, South African Medical Research Council, 7505, Tygerberg, South Africa;Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, 7505, Tygerberg, South Africa;Non-Communicable Diseases Research Unit, South African Medical Research Council, 7505, Tygerberg, South Africa;Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Boundary Road, 7700, Newlands, South Africa;

关键词: Obesity;    Insulin resistance;    Glucocorticoid receptor;    FKBP5;    DNA methylation;    Adipose tissue;   

DOI  :  10.1186/s13148-020-00932-3

来源: Springer

【 摘 要 】

BackgroundDisruption 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.MethodsAbdominal 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.ResultsTwo 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.ConclusionsThese 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

【 授权许可】

CC BY