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

BAM15: an innovative therapeutic approach to manage PCOS metabolic features associated with PCOS?  (#92)

Valentina Rodriguez Paris 1 , Stephanie J Alexopoulos 2 , Ying Hu 1 , Divya P Shah 2 , Ali Aflatounian 1 , Melissa C Edwards 1 , Michael J Bertoldo 1 , Robert B Gilchrist 1 , Kyle L Hoehn 2 , Kirsty A Walters 1
  1. School of Women's & Children's Health, University of New South Wales, Sydney, NSW 2052, Australia
  2. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia

Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous disorder characterized by endocrine, reproductive and metabolic abnormalities. To date, there is no cure for PCOS, and existing treatments are suboptimal. Obesity and adverse metabolic features are prevalent in PCOS patients, but weight loss has a favorable effect on PCOS features. However, dietary interventions aimed at weight loss are difficult to maintain long-term. Interestingly, recent data from animal studies has shown that a small molecule mitochondrial uncoupler, BAM15, is an effective approach to pharmacologically treat obesity and metabolic diseases. Therefore, this study aimed to investigate the efficacy of BAM15 to improve PCOS-traits in a hyperandrogenic PCOS mouse model. As expected, exposure of female mice to dihydrotestosterone (DHT) induced the PCOS metabolic features of increased body weight (P<0.05), lean mass (P<0.001), increased parametrial and mesenteric fat pad weights (P<0.05) and adipocyte hypertrophy (P<0.05). DHT-induced PCOS mice also exhibited increased HOMA-IR, cholesterol and fasting triglyceride levels and hepatic steatosis (all P<0.05). Conversely, DHT-induced PCOS females treated with BAM15 displayed lowered body weights similar to controls, a significant decrease in parametrial and mesenteric fat depot weights (P<0.05) and a slight decrease of adipocyte hypertrophy. Likewise, BAM15 treatment moderately decreased HOMA-IR, cholesterol and fasting triglyceride levels and the degree of hepatic steatosis observed in PCOS females, to levels comparable with controls. Furthermore, PCOS mice displayed the reproductive PCOS features of irregular cycles and anovulation, which were not ameliorated by BAM15 treatment. These findings demonstrate that the pharmacologic mitochondrial uncoupler BAM15 ameliorated metabolic PCOS features in a preclinical mouse model of PCOS. Altogether, these data provide evidence to support BAM15 as a possible innovative therapeutic approach to manage PCOS associated metabolic features.