Androgen Actions in Adipose Tissue, But Not Skeletal Muscle, are Involved in the Development of Metabolic PCOS Features in a Mouse Model

Background: Polycystic ovary syndrome (PCOS) is a common disorder characterised by endocrine, reproductive and metabolic dysfunction. Hyperandrogenism is a key diagnostic trait and evidence supports a role for androgen receptor (AR) mediated actions in PCOS pathogenesis. Aberrant AR signalling in adipose tissue and muscle have been proposed as being involved in PCOS pathogenesis, but their importance and the precise AR signalling mechanisms involved remain undefined. Aim: To investigate the role of AR signalling in white adipose tissue (WAT), brown adipose tissue (BAT) and skeletal muscle in the development of PCOS. Method: WT, global androgen receptor knockout (ARKO) and skeletal muscle-specific (SkMARKO) mice were exposed to DHT to induce PCOS. ARKO (AR−/−) WAT/BAT was transplanted into WT (AR+/+) DHT-induced PCOS females, and WT WAT/BAT was transplanted into ARKO DHT-induced PCOS females. After 12 weeks of DHT exposure all mice were assessed for the presence of reproductive and metabolic PCOS traits. Results: DHT exposure in WT females induced key reproductive and metabolic PCOS traits. SkMARKO mice treated with DHT displayed a similar phenotype to DHT-treated WT females, with full development of reproductive and metabolic PCOS traits. Transplantation of ARKO WAT/BAT into DHT-treated WT females prevented the development of some metabolic PCOS features, as mice exhibited a significantly lower body weight (P<0.05), decreased visceral adiposity (P<0.05), and smaller adipocyte size (P<0.05) compared to DHT-treated WT females with sham surgery. In contrast, reproductive PCOS traits were not ameliorated by WAT or BAT transplantation. Furthermore, DHT exposure in ARKO female mice transplanted with WT WAT/BAT did not lead to the development of PCOS traits. Conclusion: WAT and BAT, but not skeletal muscle, are key sites of AR-mediated actions involved in the development of metabolic PCOS traits. These data support targeting adipocyte AR-driven pathways in future research aimed at developing novel therapeutic interventions for PCOS.