Androgen Receptor Inhibition Prevents Dihydrotestosterone-induced Hepatic Insulin Resistance
Obi, Chukwuemeka   (Johns Hopkins University)
Mentor: Wu, Sheng (Johns Hopkins University School of Medicine)
Polycystic Ovarian Syndrome (PCOS) is a major cause of infertility in women and is characterized by hyperandrogenemia (HA), oligo/anovulation, and polycystic ovaries. Obesity, type 2 diabetes, and insulin resistance are also associated with PCOS. However, little is understood about PCOS and insulin action of hyperandrogenic females. On the other hand, Hyperandrogenemia (HA) has been shown to cause these impaired glucose tolerance and insulin resistance in women and in female rodent models. However, the mechanism of this HAinduced metabolic dysfunction is not fully understood. Previous laboratory studies showed that DHT hyperandrogenic mice displayed impaired glucose tolerance (IGT), impaired insulin sensitivity (IIS) and impaired pyruvate tolerance (IPT) through cytosolic and nuclear mechanistic pathways by binding Androgen Receptor (AR). Our previous findings have shown that the liver is a primary target of HA-induced metabolic dysfunction and that low dose DHT in mice caused insulin resistance. The goal of this study was to determine the effect of androgen receptor inhibition on DHT-induced impaired glucose tolerance and hepatic insulin resistance using flutamide, an androgen receptor antagonist. We hypothesized that androgen receptor inhibition would prevent DHT-induced hepatic insulin resistance. Metabolic (GTT, ITT, PTT), biochemical, and molecular (Western blots) assays were performed on the mice and tissue samples obtained from the mice. Molecular (Western blots) assays were performed on the liver tissue samples obtained from the low dose DHT and control mice. Additionally, a low dose DHT cell model using H2.35 female mouse hepatocytes was developed to study androgen and AR effects on insulin signaling. DHT mice displayed hepatic insulin resistance and increased gluconeogenesis through nuclear and cytosolic mechanistic pathways. However, with flutamide treatment, hepatic insulin resistance and increased gluconeogenesis were reduced. In the cell model, the DHTinduced hepatocyte insulin resistance and increased gluconeogenesis was prevented by AR antagonist, flutamide indicating AR in the liver is a key driver of HA-induced whole body and hepatic metabolic dysfunction and insulin resistance. Thus, AR could be a potential target for PCOS therapeutic intervention against insulin resistance.