Melissa H. Broeks1*, Vera Sommers2*, Jan Kroon1, Frank Claessens2, Onno C. Meijer1‡, Vanessa Dubois2,3‡
(1) Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
(2) Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
(3) Laboratory of Basic and Translational Endocrinology, Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
*,‡ These authors contributed equally
Glucocorticoid receptor (GR) signaling exhibits sexually dimorphic effects, particularly in metabolic tissues. We previously demonstrated that chronic GR-activation in the male mouse liver induces upregulation of the androgen receptor (AR), subsequently altering the GR-dependent transcriptional response[1]. To further investigate the extent of androgen-glucocorticoid crosstalk in metabolic tissues, fourteen-week-old C57BL/6J male mice that underwent orchiectomy (ORX) were treated with either 5α-dihydrotestosterone (DHT, 10 mg silastic implant), corticosterone (CORT, 12.5 mg pellet), or both for 14 days. We previously reported that DHT modulated CORT-effects on both lean and fat mass[2]. Here, we aim to further elucidate the transcriptomic profile in livers of these mice.
RNA-sequencing was performed on livers from SHAM (n=5), ORX (n=5), ORX+DHT (n=4), ORX+CORT (n=5) and ORX+CORT+DHT (n=5) groups. Principal component analysis revealed that DHT partially normalized ORX-induced transcriptional effects. Using differential expression analysis, we delineated five gene categories: synergy (n=189), antagonism of CORT by DHT (n=260), antagonism of DHT by CORT (n=9), robust DHT effects (n=18) and robust CORT effects (n=89). Cross-validation of synergy and CORT-antagonism categories with previous liver transcriptome data[1] confirmed potential targets of androgen-glucocorticoid crosstalk. These findings suggest that AR-signaling modulates GR transcriptional responses through two mechanisms: androgen-dependent potentiation of GR-signaling (synergy) and androgen-mediated suppression on GR-signaling (antagonism of CORT by DHT). As a potential mechanism of crosstalk we found that CORT-treatment increased AR protein expression in liver (main effect 2-way ANOVA, p=0.0046). Overall, our data highlight the modulating role for androgens in hepatic GR-signaling, that may contribute to sexually dimorphic metabolic responses to glucocorticoids.
[1] Buurstede, J. C., Paul, S. N., De Bosscher, K., Meijer, O. C., & Kroon, J. (2022). Hepatic glucocorticoid- induced transcriptional regulation is androgen- dependent after chronic but not acute glucocorticoid exposure. FASEB J, 36:e22251. doi:10.1096/fj.202101313R
[2] Sommers, V., David, K., Helsen, C., Moermans, K., Stockmans, I., Ferrari, G., … & Dubois, V. (2025). Androgens differentially modulate glucocorticoid effects on adipose tissue and lean mass. Journal of Endocrinology, 264:e240061. https://doi.org/10.1530/JOE-24-0061