Hepatic Androgen Receptor Modulates Hyperandrogenemia-Induced Glucose Metabolic Dysfunction and Hepatic Insulin Resistance
Presentation Number: OR13-2
Date of Presentation: April 2nd, 2017
Stanley Andrisse*1 and Sheng Wu2
1Johns Hopkins University School of Medicine, Baltimore, MD, 2Johns Hopkins University School, Baltimore, MD
Hyperandrogenemia (HA) has been shown to cause impaired glucose tolerance and insulin resistance in women and in female rodent models. The mechanism of this HA-induced metabolic dysfunction is not fully understood. We developed a mouse model that displayed pathophysiological serum androgen levels with normal body mass to ensure that the phenotypes were directly from androgens and not an indirect consequence of obesity. DHT mice demonstrated impaired glucose, insulin and pyruvate tolerance, and lowered hepatic insulin action. Our previous findings have shown that the liver is a primary target of HA-induced metabolic dysfunction. The goal of this study was to determine the role of hepatic androgen receptor (AR) in DHT-induced impaired glucose tolerance and hepatic insulin resistance. Molecular (Western blots, qRT-PCR, immunoprecipitation (IP), and chromatin IP) 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. Low dose DHT lowered hepatic insulin stimulated PI3K activity, p-AKT and p-FOXO1 but had no effect on p-Y-IRS1/2 compared to control. DHT mice. Mechanistically, DHT increased hepatic AR binding to phosphoinositide-3-kinase (PI3K)-p85 resulting in dissociation of PI3K-p85 from PI3K-p110 leading to reduced PI3K activity and decreased p-AKT, thus lowered insulin action. In addition, DHT increased gluconeogenesis via AR-specific transcriptional upregulation of gluconeogenic enzymes (G6Pase and PEPCK) and co-activators (FOXO1 and CREB). In the cell model, the DHT-induced hepatocyte insulin resistance and increased gluconeogenesis was reversed by AR antagonist, flutamide. These findings suggest that AR in the liver is a key driver of HA-induced whole body and hepatic metabolic dysfunction and insulin resistance. AR acts both in the nucleus and the cytosol to enact these detrimental effects on metabolism.
Nothing to Disclose: SA, SW