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

Abstract

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

Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review

“…Association between DNA methylation with fasting glucose were found for ADIPOQ (positive association) and TNFA (negative association), although there is some contradicting information regarding ADIPOQ since another study found no relationship between ADIPOQ and any glycemic parameters ( 53 ). HOMA-IR showed a positive correlation with methylation at INSR , SLC2A4 ( 56 ) and FKBP5 ( 57 ).…”

“…Altogether, these studies profiled DNA methylation for 14 genes with established roles in AT and/or glycemic control, ranging from adipokines ( TNFA, ADIPOQ ) to a glucose transporter ( SLC2A4 ). Of these 14 genes ( Table 1 ), ADIPOQ and TNFA had gene methylation frequency altered in MUHO ( 59 ), whilst FGF21 ( 58 ), INSR, SLC2A4 ( 56 ) and FKBP5 ( 57 ) were associated with DMRs that correlated negatively with gene expression. Meanwhile, MCP1 ( 59 ), HIF3A ( 55 ), LEP ( 53 ), C3 ( 52 ), SREBF , ABCG1 ( 54 ), PIK3R1 ( 56 ) and GR ( 57 ) showed no differences between subjects with MUHO and NW/MHO controls, or showed no correlation with glycemic parameters.…”

“…Of these 14 genes ( Table 1 ), ADIPOQ and TNFA had gene methylation frequency altered in MUHO ( 59 ), whilst FGF21 ( 58 ), INSR, SLC2A4 ( 56 ) and FKBP5 ( 57 ) were associated with DMRs that correlated negatively with gene expression. Meanwhile, MCP1 ( 59 ), HIF3A ( 55 ), LEP ( 53 ), C3 ( 52 ), SREBF , ABCG1 ( 54 ), PIK3R1 ( 56 ) and GR ( 57 ) showed no differences between subjects with MUHO and NW/MHO controls, or showed no correlation with glycemic parameters. Association between DNA methylation with fasting glucose were found for ADIPOQ (positive association) and TNFA (negative association), although there is some contradicting information regarding ADIPOQ since another study found no relationship between ADIPOQ and any glycemic parameters ( 53 ).…”

“…DNA methylation at the promoter regions of these genes showed a negative correlation with expression of the corresponding genes ( 56 , 58 ). Importantly, these targeted studies found significant correlations between glycemic parameters (such as fasting glucose or HbA1c), insulin resistance measurements (such as HOMA-IR) or insulin sensitivity measurements (such as the Matsuda index or QUICKI) with levels of DNA methylation for ADIPOQ , TNFA , FKBP5 , INSR and SLC2A4 ( 56 , 57 , 59 ). These comparisons draw some parallels between glucose levels and DNA gene methylation changes in several tissue types from in vitro studies ( 142 , 143 ).…”

Association of CIDEB gene promoter methylation with overweight or obesity in adults

“…To investigate the relationship between obesity and insulin resistance, Aneta Cierzniak et al [ 33 ] collected VAT and SAT from 45 patients undergoing abdominal surgery. Tarryn Willmer et al [ 34 ] obtained abdominal SAT and gluteal SAT from 27 obese and 27 normal weight urban-dwelling South African women and found that the methylation level of FK506-binding protein 51 kDa (FKBP5) gene was associated with obesity and insulin resistance. In conclusion, the sample size of this study is moderate, and the results of this study have a certain reference value, which can provide a theoretical basis for finding targets for the treatment of obesity.…”