Fig. 7

Schematic proposed model of study findings showing how metabolic stressors lead to obesity and inflammation-induced downregulation of GR, possibly through glucocorticoid resistance and induction of the non-ligand binding GRβ isoform, and consequently, hypermethylation of FKBP5 at selected CpGs (CpG542 and CpG543) located within intron 7 in subcutaneous adipose tissue. Reduced FKBP5 mRNA expression would result in a loss of the ultra-short negative feedback loop between FKBP5 and GR (grey arrows), thus altering the biologic response to glucocorticoids. DNA methylation alterations in FKBP5 CpG542/3 are associated with increased clinical risk factors for disease, including adiposity (high BMI, WC and leptin), inflammation (high CRP) and insulin resistance (elevated fasting insulin and HOMA-IR, low adiponectin) and reduced insulin sensitivity. This figure was created using BioRender (https://biorender.com/)