Androgen Receptor Roles in Insulin Resistance and Obesity
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. Androgen-deprivation therapy (ADT) is the first-line treatment and fundamental management for men with advanced PCa to suppress functions of androgen/androgen receptor (AR) signaling. ADT is effective at improving cancer symptoms and prolonging survival. However, epidemiological and clinical studies support the notion that testosterone deficiency in men leads to the development of metabolic syndrome that increases cardiovascular disease risk. The underlying mechanisms by which androgen/AR signaling regulates metabolic homeostasis in men are complex, and in this review, we discuss molecular mechanisms mediated by AR signaling that link ADT to metabolic syndrome. Results derived from various AR knockout mouse models reveal tissue-specific AR signaling that is involved in regulation of metabolism. These data suggest that steps be taken early to manage metabolic complications associated with PCa patients receiving ADT, which could be accomplished using tissue-selective modulation of AR signaling and by treatment with insulin-sensitizing agents.
Prostate cancer (PCa) is the second leading cause of cancer-related mortality and the most common malignancy in men in the U.S.. Androgen-deprivation therapy (ADT) to suppress PCa was initially demonstrated by Huggins and Hodges in 1941 and remains as the standard treatment for PCa. ADT is accomplished with surgical castration (bilateral orchiectomy) or chemical castration with gonadotropin-releasing hormone (GnRH) agonists to suppress binding of androgen to the androgen receptor (AR). Although ADT improves survival at all stages of PCa, it leads to severe hypogonadism with different adverse effects, including unfavorable metabolic alterations. Treatment of the metabolic complications of ADT has been considered and has become increasingly important. Metabolic syndrome is a complex disorder consisting of abdominal obesity, dyslipidemia, insulin resistance, and hypertension. Obese individuals are more prone to develop insulin resistance compared with nonobese individuals. Insulin resistance promotes metabolic complications including elevated circulating triglycerides, reduced HDL, elevated fasting blood glucose levels, and high blood pressure. These metabolic abnormalities, in conjunction with abdominal obesity, represent the classical features of metabolic syndrome. Metabolic syndrome is an important risk factor for cardiovascular disease and associated morbidity and mortality in individuals with or without diabetes.
In this article, we will discuss the molecular aspects of mechanisms linking ADT to metabolic syndrome by focusing on evidence derived from AR-knockout (ARKO) mouse models.
Abstract and Introduction
Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. Androgen-deprivation therapy (ADT) is the first-line treatment and fundamental management for men with advanced PCa to suppress functions of androgen/androgen receptor (AR) signaling. ADT is effective at improving cancer symptoms and prolonging survival. However, epidemiological and clinical studies support the notion that testosterone deficiency in men leads to the development of metabolic syndrome that increases cardiovascular disease risk. The underlying mechanisms by which androgen/AR signaling regulates metabolic homeostasis in men are complex, and in this review, we discuss molecular mechanisms mediated by AR signaling that link ADT to metabolic syndrome. Results derived from various AR knockout mouse models reveal tissue-specific AR signaling that is involved in regulation of metabolism. These data suggest that steps be taken early to manage metabolic complications associated with PCa patients receiving ADT, which could be accomplished using tissue-selective modulation of AR signaling and by treatment with insulin-sensitizing agents.
Introduction
Prostate cancer (PCa) is the second leading cause of cancer-related mortality and the most common malignancy in men in the U.S.. Androgen-deprivation therapy (ADT) to suppress PCa was initially demonstrated by Huggins and Hodges in 1941 and remains as the standard treatment for PCa. ADT is accomplished with surgical castration (bilateral orchiectomy) or chemical castration with gonadotropin-releasing hormone (GnRH) agonists to suppress binding of androgen to the androgen receptor (AR). Although ADT improves survival at all stages of PCa, it leads to severe hypogonadism with different adverse effects, including unfavorable metabolic alterations. Treatment of the metabolic complications of ADT has been considered and has become increasingly important. Metabolic syndrome is a complex disorder consisting of abdominal obesity, dyslipidemia, insulin resistance, and hypertension. Obese individuals are more prone to develop insulin resistance compared with nonobese individuals. Insulin resistance promotes metabolic complications including elevated circulating triglycerides, reduced HDL, elevated fasting blood glucose levels, and high blood pressure. These metabolic abnormalities, in conjunction with abdominal obesity, represent the classical features of metabolic syndrome. Metabolic syndrome is an important risk factor for cardiovascular disease and associated morbidity and mortality in individuals with or without diabetes.
In this article, we will discuss the molecular aspects of mechanisms linking ADT to metabolic syndrome by focusing on evidence derived from AR-knockout (ARKO) mouse models.
Source...