The Role of Osteoblasts and Sex Hormones in Glucocorticoid-induced Metabolic Dysfunction

Glucocorticoids are some of the most widely prescribed medications world-wide, however their use is often limited by unwanted effects. Our team has previously shown that the adverse metabolic outcomes of glucocorticoids are in part mediated via the osteoblast and its specific product, osteocalcin. To further investigate this novel relationship, I aimed to: a) develop a glucocorticoid delivery system relevant to the therapeutic situation in humans and b) establish a reliable approach to osteocalcin gene therapy using an adeno-associated viral vector. Delivery of corticosterone, the major glucocorticoid in rodents, to wild-type mice via the drinking water reproduced both the adverse metabolic changes and the diurnal variation seen in humans during glucocorticoid therapy. My studies further confirmed the novel concept that some of the adverse metabolic effects of glucocorticoid therapy are mediated via the osteoblast. While gene therapy via adeno-associated viral injection proved to be a reliable method of osteo¬calcin delivery to glucocorticoid-treated mice, my experiments did not support the notion that osteocalcin replacement in glucocorticoid-treated animals protects mice from dysmetabolism. In the course of my investigations I discovered that in contrast to male mice, who rapidly developed insulin resistance and increased fat accrual, female mice remained metabolically healthy despite prolonged treatment with corticosterone. Ovariectomy did not change this resistance to glucocorticoids, excluding an oestrogen-related effect. On the other hand, castrated male mice no longer developed signs of dysmetabolism as a result of corticosterone treatment. However, when castrated male or female mice were implanted with dihydrotestosterone, treatment with corticosterone rendered the mice again severely obese and insulin resistant, resulting in hyperinsulinemia, hyperleptinemia and brown adipose tissue dysfunction. Dihydrotestosterone was also found to directly interfere in the leptin lowering capacity of insulin in the context of glucocorticoid excess. My results indicate that androgens strongly potentiate the adverse metabolic side effects of glucocorticoids, which may have clinical implications for this prevalent global economic and health burden