11-Oxygenated Androgens Inhibit Brown Adipose Tissue Differentiation.

CONTEXT: Women with polycystic ovary syndrome (PCOS) and PCOS animal models have diminished brown adipose tissue (BAT) activity, potentially contributing to metabolic dysfunction. Besides classical androgens, adrenal 11-oxygenated androgens are elevated in women with PCOS. However, it remains unknown whether these 11-oxygenated androgens affect BAT metabolism. OBJECTIVE: To study the effects of 11-ketotestosterone (KT) and 11-ketodihydrotestosterone (KDHT) on BAT metabolism. METHODS: The female mouse brown adipocyte cell line T37i was treated with increasing concentrations (0.1-10†µM) of testosterone (T), dihydrotestosterone (DHT), KT, or KDHT during or after differentiation. In addition, female mice received a daily injection of vehicle, DHT, KT, or KDHT (100†µg) for 1 day or 1 week. Adipose depots were collected for RNA sequencing (RNAseq) analysis and Gene Set Enrichment Analysis (GSEA). RESULTS: During differentiation, T, KT, DHT, and KDHT treatment of T37i cells dose-dependently reduced lipid droplet accumulation, and downregulated mRNA expression of adipogenic markers by up to 50%, with KDHT having the weakest effect. In mature T37i cells, only the high concentrations of these androgens exhibited inhibitory effects. RNAseq analysis revealed that DHT exposure induced the most differentially regulated genes in BAT, followed by KT and KDHT treatment. GSEA indicated that 1-day treatment with DHT and KT, but not KDHT, resulted in the downregulation of metabolic pathways in BAT. CONCLUSION: 11-Oxygenated androgens at high concentrations directly inhibit brown adipocyte differentiation in vitro and KT acutely downregulates BAT metabolic transcriptome in vivo, a result not observed with KDHT. These findings suggest that elevated 11-oxygenated androgens may impair BAT function, contributing to metabolic complications associated with hyperandrogenic conditions, including PCOS.