Androgens differentially modulate glucocorticoid effects on adipose tissue and lean mass

Glucocorticoids and androgens affect each other in several ways. In metabolic organs, such as adipose tissue and the liver, androgens enhance glucocorticoid-induced insulin resistance and promote fat accumulation in male mice. However, the direct contribution of the androgen receptor (AR) to these effects is unknown. Furthermore, it is unclear whether the potentiating effect of androgens on glucocorticoid signaling in fat extends to other tissues, such as skeletal muscle and bone. In this study, we used two complementary models for androgen deprivation (orchidectomy and chemical castration) to investigate the effects of dihydrotestosterone (DHT) on corticosterone (CORT). We found that after 2 weeks of intervention, DHT alone did not affect fat mass but increased lean mass, while CORT increased fat mass and decreased lean mass. Co-supplementation with DHT counteracted the CORT effect on lean mass but enhanced its effect on adiposity. Glucocorticoid induction of Gilz, Fkbp5 and Mt2a in gonadal white adipose tissue depended on the presence of androgens, while in interscapular brown adipose tissue, these genes responded to glucocorticoids also without androgens. To directly assess the impact of the AR on the glucocorticoid response, male global AR knock-out mice were exposed to CORT and compared to WT littermates. CORT exposure resulted in an increase in fat mass and a decrease in lean mass in both genotypes. In conclusion, functional AR signaling is dispensable for the metabolic response to glucocorticoids. However, androgen signaling in WT mice modulates glucocorticoid response in a tissue-dependent manner, by counteracting lean mass and potentiating fat mass effects.