Mitochondrial Uncoupler BAM15 Ameliorates Associated Metabolic PCOS Traits in a Hyperandrogenic PCOS Mouse Model

Abstract

Background: Polycystic ovary syndrome (PCOS) is a common endocrine condition characterized by endocrine, reproductive and metabolic abnormalities. 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 beneficial effect on PCOS features. However, dietary interventions aimed at weight loss are difficult to sustain long-term. Interestingly, recent data from animal studies has shown that a mitochondrial uncoupler, BAM15, is an effective approach to pharmacologically treat obesity and metabolic diseases. Aim: To investigate the efficacy of BAM15 to ameliorate PCOS-traits in a PCOS mouse model. Method: The effect of BAM15 treatment on metabolic and reproductive PCOS features were evaluated in dihydrotestosterone (DHT)-induced PCOS mice fed a standard chow diet ± BAM15 for 10 weeks. Results: As expected, exposure of female mice to 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 with controls, a significant decrease in parametrial and mesenteric fat depot weights (P<0.05) and reduced adipocyte hypertrophy. Likewise, BAM15 treatment decreased HOMA-IR, cholesterol and fasting triglyceride levels and the degree of hepatic steatosis observed in PCOS females, to levels comparable with control females. Lastly, PCOS mice presented the reproductive PCOS traits of irregular cycles and ovulatory dysfunction, though BAM15 treatment did not improve these PCOS features. Conclusion: These findings demonstrate that the pharmacologic mitochondrial uncoupler BAM15 is able to ameliorate metabolic PCOS features in a PCOS mouse model. These data provide evidence to support BAM15 as a potential innovative therapeutic approach to manage associated metabolic PCOS features.