Androgen signaling in adipose tissue, but less likely skeletal muscle, mediates development of metabolic traits in a PCOS mouse model.

Polycystic ovary syndrome (PCOS) is a common, multifactorial disorder characterized by endocrine, reproductive, and metabolic dysfunction. As the etiology of PCOS is unknown, there is no cure and symptom-oriented treatments are suboptimal. Hyperandrogenism is a key diagnostic trait, and evidence suggests that androgen receptor (AR)-mediated actions are critical to PCOS pathogenesis. However, the key AR target sites involved remain to be fully defined. Adipocyte and muscle dysfunction are proposed as important sites involved in the manifestation of PCOS traits. We investigated the role of AR signaling in white adipose tissue (WAT), brown adipose tissue (BAT), and skeletal muscle in the development of PCOS in a hyperandrogenic PCOS mouse model. As expected, dihydrotestosterone (DHT) exposure induced key reproductive and metabolic PCOS traits in wild-type (WT) females. Transplantation of AR-insensitive ( AR -/- ) WAT or BAT from AR knockout females (ARKO) into DHT-treated WT mice ameliorated some metabolic PCOS features, including increased body weight, adiposity, and adipocyte hypertrophy, but not reproductive PCOS traits. In contrast, DHT-treated ARKO female mice transplanted with AR-responsive ( AR +/+ ) WAT or BAT continued to resist developing PCOS traits. DHT-treated skeletal muscle-specific AR knockout females (SkMARKO) displayed a comparable phenotype with that of DHT-treated WT females, with full development of PCOS traits. Taken together, these findings infer that both WAT and BAT, but less likely skeletal muscle, are key sites of AR-mediated actions involved in the experimental pathogenesis of metabolic PCOS traits. These data further support targeting adipocyte AR-driven pathways in future research aimed at developing novel therapeutic interventions for PCOS. NEW & NOTEWORTHY Hyperandrogenism is a key feature in the pathogenesis of polycystic ovary syndrome (PCOS); however, the tissue sites of androgen receptor (AR) signaling are unclear. In this study, AR signaling in white and brown adipose tissue, but less likely in skeletal muscle, was found to be involved in the development of metabolic PCOS traits, highlighting the importance of androgen actions in adipose tissue and obesity in the manifestation of metabolic disturbances.