? It is well-known that patients with cortisol excess develop Cushing's syndrome with central obesity and insulin resistance. However, recent studies in humans and rodents suggest a role for tissue rather than plasma cortisol excess in the development of idiopathic obesity and the metabolic syndrome via intracellular steroid reactivation of inert circulating cortisone (11-dehydrocorticosterone in rodents) into active cortisol (corticosterone) by an enzyme called 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In support of this, mice with excess of this enzyme in their fat and liver cells develop insulin resistance and metabolic syndrome through increasing intracellular active cortisol levels. Similarly, we used an animal model of type 2 diabetes, called obese db/db mice and found that they have high liver and fat levels of 11 beta -HSD1, which positively correlated with their insulin resistance, hyperglycemia and obesity. We and others also reported that inhibition of this enzyme increased insulin sensitivity in obese mice as well as in humans. We hypothesized that the enzyme 11beta-HSD1 determines the availability of intracellular steroids and insulin sensitivity, and further that 11beta-HSD1 could be a new therapeutic target for type 2 diabetes and obesity. We are now interested in trying to understand why increased intracellular glucocorticoid availability may contribute to insulin resistance and obesity and if endogenous manipulation and exogenous drugs aimed at reducing the tissue levels of this enzyme will improve type 2 diabetes and obesity of obese rodents. In this grant application, we will examine the effects of intracellular glucocorticoid availability on insulin signaling and glucose transport in primary cultures of mouse hepatocytes and adipocytes through manipulation of 11 beta-HSD1 activity with its inhibitor and specific siRNA silence (direct against 11 beta- HSD1 expression). Animal studies will further define the benefits of decreasing tissue glucocorticoid availability in insulin sensitivity and body weight by endogenous modulation and specific inhibition of 11 beta- HSD1 with viral-mediated siRNA technology. Our experiments will help to comprehensively elucidate the potential beneficial mechanism for selective enzyme inhibition within liver and adipose tissues as a novel therapeutic strategy for metabolic syndromes, and thus, would provide a base for the development of a specific 11 beta-HSD1 inhibitor, which can be used to target type 2 diabetes and/or obesity in humans. ? ?
