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

• Published in: American journal of physiology: endocrinology and metabolism 2022-08, Vol.323 (2), p.E145-E158
• Main Authors: Xiong, Ting, Rodriguez Paris, Valentina, Edwards, Melissa C, Hu, Ying, Cochran, Blake J, Rye, Kerry-Anne, Ledger, William L, Padmanabhan, Vasantha, Handelsman, David J, Gilchrist, Robert B, Walters, Kirsty A
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipose tissue; Adipose tissue (brown); Androgen receptors; Androgens; Body fat; Body weight; Dihydrotestosterone; Etiology; Females; Hypertrophy; Metabolism; Muscles; Musculoskeletal system; Pathogenesis; Phenotypes; Polycystic ovary syndrome; Signaling; Skeletal muscle; Therapeutic applications; Transplantation
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00418.2021

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 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 wildtype (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 to 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.