Glucocorticoid metabolism and the control of metabolic phenotype.

Obesity is associated with medical complications that include heart attacks, strokes, type 2 diabetes and the development of fatty liver disease which can progress to liver failure. The mechanisms that contribute to fat deposition within the liver are not fully understood and we believe that increased local production and / or decreased breakdown of the steroid hormone, cortisol, may contribute to the disease. In addition, cortisol acting on fat within the abdomen may fuel fatty liver disease by increasing delivery of fat precursors to the liver. Importantly, patients who either produce too much cortisol or who are prescribed large doses of steroid hormones develop many of these complications including obesity and fatty liver disease. We will use cells cultured from liver and fat to determine the effect of cortisol on fat accumulation. We will also assess the impact of modifying production and break down of cortisol. We will create rodent models in which we have genetically manipulated the enzymes that produce and breakdown cortisol. We believe that decreasing cortisol production and enhancing breakdown will have beneficial effects. Finally, we will conduct clinical studies using drugs that decrease cortisol production to see if they can decrease fat accumulation within the liver.