Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Molecular modelling using a PCOS mouse model in combination with androgen receptor knockout mouse models (ARKO) to unravel PCOS pathogenesis (#133)

Valentina Rodriguez Paris 1 , Ting Xiong 1 , Melissa C Edwards 1 2 , Blake J Cochran 3 , Kerry-Anne Rye 3 , William L Ledger 1 , Vasantha Padmanabhan 4 , David J Handelsman 2 , Robert B Gilchrist 1 , Kirsty A Walters 1 2
  1. School of Women's & Children's Health, University of New South Wales, Sydney, NSW 2052, Australia
  2. ANZAC Research Institute, University of Sydney , Sydney, NSW 2139, Australia
  3. School of Medical Sciences , University of New South Wales, Kensington, NSW, Australia
  4. Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder characterized by endocrine, reproductive and metabolic dysfunction. The etiology of PCOS is poorly understood, however, hyperandrogenism is a key diagnostic feature and evidence supports a role for androgen receptor (AR) mediated actions in PCOS pathogenesis. Aberrant AR signaling in adipose tissue and muscle are proposed as being implicated in the manifestation of PCOS, but their significance and the precise AR signaling mechanisms involved remain unclear. This study investigated the role of AR signaling in white adipose tissue (WAT), brown adipose tissue (BAT) and skeletal-muscle in the development of PCOS traits. We exposed wildtype (WT), global androgen receptor knockout (ARKO) and skeletal muscle specific ARKO (SkMARKO) mice to dihydrotestosterone (DHT) to induce PCOS traits. ARKO (AR-/-) WAT/BAT were transplanted into WT (AR+/+) DHT-induced PCOS females, and WT WAT/BAT were transplanted into ARKO DHT-induced PCOS females. After 12 weeks of DHT exposure, reproductive and metabolic PCOS traits were assessed. DHT induced key reproductive and metabolic PCOS traits in WT females. SkMARKO mice treated with DHT displayed a similar phenotype to DHT-treated WT females, with full development of reproductive and metabolic PCOS features. Transplantation of ARKO WAT/BAT into DHT-treated WT females prevented the development of some metabolic PCOS features, as mice displayed significantly lower body weights (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. However, reproductive PCOS traits were not ameliorated by ARKO WAT or BAT transplantation. Furthermore, DHT exposed ARKO female mice transplanted with WT WAT/BAT did not develop PCOS traits. In summary, WAT and BAT, but not skeletal muscle, are key sites of AR-mediated actions involved in the development of PCOS-associated metabolic traits. These findings support targeting adipocyte AR-driven pathways in future research for the development of novel therapeutic interventions for PCOS.