Glucocorticoids (GCs) are important endocrine regulators of a wide range of physiological processes ranging from immune function to glucose and lipid metabolism. For decades, synthetic glucocorticoids such as dexamethasone have been the cornerstone for the clinical treatment of inflammatory bowel diseases (IBD). A previous study has shown that farnesoid X receptor (FXR) enhances the transcription of NR3C1 gene, which encodes for human GR, by binding to a conserved FXR response element (FXRE) in the distal promoter of this gene. In the present study we demonstrate that FXR promotes the resolution of colitis in rodents by enhancing Gr gene transcription. We used the chromatin conformation capture (3C) assay to demonstrate that this FXRE is functional in mediating a head-to-tail chromatin looping, thus increasing Gr transcription efficiency. These findings underscore the importance of FXR/GR axis in the control of intestinal inflammation.

Recent data have demonstrated that triple negative breast cancer (TNBC) with high glucocorticoid receptor (GR) expression are associated to therapy resistance and increased mortality. Given that GR alternative splicing generates mainly GRα, responsible of glucocorticoids action, we investigated its role in the regulation of RACK1 (Receptor for Activated C Kinase 1), a scaffolding protein with a GRE (Glucocorticoid Response Element) site on its promoter and involved in breast cancer cells migration and invasion. We provide the first evidence that GRα transcriptionally regulates RACK1 by a mechanism connected to SRSF3 splicing factor, which promotes GRα, essential for RACK1 transcriptional regulation and consequently for cells migration. We also establish that this mechanism can be positively regulated by cortisol. Hence, our data elucidate RACK1 transcriptional regulation and demonstrate that SRSF3 involvement in cells migration implies its role in controlling different pathways thus highlighting that new players have to be considered in GR-positive TNBC.

Osteoarthritis is associated with intrauterine growth retardation (IUGR) and abnormal glucose metabolism. Our laboratory previously reported that prenatal caffeine exposure (PCE) can induce intrauterine maternal glucocorticoid (GC) overexposure in IUGR offspring and increase susceptibility to osteoarthritis after birth. In the present study, we demonstrated the essential role of glucose transporter 1 (GLUT1) programming changes in the increased matrix degradation of articular cartilage and susceptibility to osteoarthritis in female PCE adult offspring. In vivo, we found that PCE decreased the matrix content but did not significantly change the expression of matrix degradation-related genes in the articular cartilage of female fetal rats. The decreased expression of IGF1 and GLUT1 and the content of advanced-glycation-end-products (AGEs) were also detected. At different postnatal stages (2, 6, and 12 weeks), the cartilage matrix content decreased while the degradation-related genes expression increased in the PCE group. Meanwhile, the expression of IGF1 and GLUT1 and AGEs content in the local cartilage increased. In vitro, the expression levels of IGF1 and GLUT1 were inhibited by corticosterone but remained unchanged under caffeine treatment. Exogenous IGF1 can reverse the corticosterone-induced decrease in GLUT1 expression and promote AGEs production, while mifepristone (a glucocorticoid receptor inhibitor) reversed the corticosterone-induced low expression of IGF1 and GLUT1. Exogenous AGEs can increase the expression of inflammatory factors (IL-6 and TNF-α) and degradation-related genes, and decrease the matrix synthesis-related genes expression in chondrocyte. In conclusion, the GC-IGF1-GLUT1 axis mediated intrauterine dysplasia of articular cartilage, increased accumulation of AGEs and matrix degradation after birth in PCE female offspring, thereby increasing their susceptibility to osteoarthritis in adulthood.

Glucocorticoids regulate numerous processes in human physiology, but deregulated or excessive glucocorticoid receptor (GR) signaling contributes to the development of various pathologies including metabolic syndrome. For this reason, GR antagonists have considerable therapeutic value. Yet, the only GR antagonist that is clinically approved to date - mifepristone - exhibits cross-reactivity with other nuclear steroid receptors like the progesterone receptor. In this study, we set out to identify novel selective GR antagonists by combining rational chemical design with an unbiased in vitro and in vivo screening approach. Using this pipeline, we were able to identify CORT125329 as the compound with the best overall profile from our octahydro series of novel GR antagonists, and demonstrated that CORT125329 does not exhibit cross-reactivity with the progesterone receptor. Further in vivo testing showed beneficial activities of CORT125329 in models for excessive corticosterone exposure and short- and long-term high-fat diet-induced metabolic complications. Upon CORT125329 treatment, most metabolic parameters that deteriorated upon high-fat diet feeding were similarly improved in male and female mice, confirming activity in both sexes. However, some sexually dimorphic effects were observed including male-specific antagonism of GR activity in brown adipose tissue and female-specific lipid lowering activities after short-term CORT125329 treatment. Remarkably, CORT125329 exhibits beneficial metabolic effects despite its lack of GR antagonism in white adipose tissue. Rather, we propose that CORT125329 treatment restores metabolic activity in brown adipose tissue by stimulating lipolysis, mitochondrial activity and thermogenic capacity. In summary, we have identified CORT125329 as a selective GR antagonist with strong beneficial activities in metabolic disease models, paving the way for further clinical investigation.