TISSUE-SPECIFIC MODULATION OF GLUCOCORTICOID EFFECTS BY ANDROGENS

Sex differences exist in both physiological and pathophysiological metabolic responses to glucocorticoids, suggesting a crosstalk between glucocorticoid and sex hormone signaling. In male liver and adipose tissue, androgens potentiate glucocorticoid action, while in the musculoskeletal system both hormones have opposing effects. This is in sharp contrast to the very similar mechanisms of action of their cognate receptors, the glucocorticoid (GR) and androgen (AR) receptors, which recognize nearly identical DNA response elements and recruit the same coregulators to the chromatin of their target genes. In a collaborative effort with the group of Meijer and Kroon (Leiden Univ), we aim to unravel the molecular mechanisms underlying GR-AR interaction and explain their tissue-specific opposing interference in muscle versus their cooperative effects in liver by use of intervention studies in rodent models. The effect of orchidectomy on the metabolic response to glucocorticoids will be compared to that of genetic interventions that disrupt AR functioning. We will assess how transcriptomes and cistromes react to androgen deprivation/complementation in combination with glucocorticoid excess and further explore the underlying molecular mechanisms in appropriate cell culture experiments. Our work will generate a deeper understanding in the fundamentally complex GR signaling and may in the long run yield novel treatment strategies for a wide range of steroid hormone-driven diseases.