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. 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. 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. 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.

中文翻译：

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南非女性 FKBP5 的 DNA 甲基化：与肥胖和胰岛素抵抗的关联。

下丘脑-垂体-肾上腺 (HPA) 轴（一种与应激反应相关的神经内分泌系统）的中断已被假设为导致肥胖的发展。这可能是通过 HPA 轴调节基因响应代谢压力的表观遗传调节来介导的。本研究的目的是研究糖皮质激素受体 (GR) 及其共同伴侣 FK506 结合蛋白 51 kDa (FKBP5) 中脂肪组织库特异性 DNA 甲基化差异，这两种都是 HPA 轴的关键调节剂。腹部皮下脂肪组织 (ASAT) 和臀部皮下脂肪组织 (GSAT) 活检取自 27 名肥胖和 27 名正常体重的南非城市女性样本。DNA甲基化和基因表达分别通过焦磷酸测序和定量实时PCR测量。进行斯皮尔曼相关系数、正交偏最小二乘判别分析和多变量线性回归以评估 DNA 甲基化、信使 RNA (mRNA) 表达与肥胖和代谢功能障碍的关键指标之间的关联。与正常体重女性相比，FKBP5 内含子 7 内的两个 CpG 二核苷酸在 ASAT 和 GSAT 中均发生高甲基化，但未观察到 GR 甲基化的差异。两个 FKBP5 CpG 位点的较高甲基化百分比与两个脂肪库中的肥胖（体重指数和腰围）、胰岛素抵抗（胰岛素抵抗的稳态模型、空腹胰岛素和血浆脂肪因子）和全身炎症（c 反应蛋白）相关。GR 和 FKBP5 mRNA 水平在 GSAT 中较低，但在 ASAT 中则不然，肥胖与正常体重妇女相比。此外，FKBP5 mRNA 水平与 DNA 甲基化呈负相关，与肥胖、代谢和炎症参数呈正相关。这些发现将失调的 FKBP5 甲基化和 mRNA 表达与南非女性的肥胖和胰岛素抵抗联系起来。需要额外的研究来评估 FKBP5 与基于人群的大型样本中肥胖和相关合并症的纵向关联。