Androgen receptor (AR) signaling plays a crucial role in androgen induced metabolic dysfunction in states of elevated androgen in females. However, how AR in the liver contribute to metabolic dysfunction in states of androgen excess, such as in polycystic ovary syndrome (PCOS), is unknown. Hyperandrogenemia is one of the defining features of PCOS, and is often accompanied by hyperinsulinemia and obesity making it difficult to discern the role of androgen signaling in the development of metabolic dysfunction not secondary to impaired metabolic function. Therefore, a model that can isolate the pathophysiological effects of hyperandrogenemia from metabolic changes resulting from obesity is warranted. We observed that elevated androgen through androgen receptor in the liver contributes to impaired metabolic function. We hypothesized that in a setting of high androgen levels: 1) androgen/AR interacts with proteins upstream of AKT to interfere with insulin signaling, thus inhibiting the phosphorylation of forkhead box O1 (FOXO1), leading to increased gluconeogenesis; 2) androgen/AR regulates the cAMP-PKA (glucagon) pathway to increase activity of cAMP response element binding protein (CREB), and leading to increased glucose production; 3) AR acts as a transcription factor regulating Foxo1 and Creb gene expression to increase gluconeogenesis; 4) induced metabolic pathology can be corrected or improved by acute deletion of AR thus pointing the way to therapeutic interventional strategies. We will focus on the role of pathophysiological androgen levels acting via AR in the liver. Approaches will use genetic deletion of AR developmentally or acutely in liver in elevated androgen mouse models.
Aim1 will focus on the liver (mouse and human hepatocytes) by defining the role of hepatocyte extranuclear AR in androgen induced metabolic dysfunction.
Aim 2 will determine whether nuclear AR is required for androgen induced gluconeogenesis.
Aim 3 will focus on whether metabolic dysfunction associated with androgen excess can be corrected or rescued by acute deletion of hepatic AR. Together these Aims will elucidate the role of AR in mediating the pathogenic effects of androgen excess in contributing to female metabolic dysfunction.
Hyperandrogenemia is a fundamental aspect seen in PCOS and congenital adrenal hyperplasia (CAH). It imposes metabolic dysfunction and infertility. The proposed studies are significant because they may lead to identification of molecular targets, and novel therapeutic approaches for the treatment of androgen related human metabolic dysfunction.
