Glucocorticoid metabolism and the control of metabolic phenotype.

肥胖与医学并发症有关，包括心脏病发作、中风、2型糖尿病和脂肪肝的发展，后者可能发展为肝功能衰竭。导致肝脏脂肪沉积的机制尚不完全清楚，我们认为局部分泌增加和/或类固醇激素皮质醇的分解减少可能是导致该病的原因之一。此外，作用于腹部脂肪的皮质醇可能会增加脂肪前体向肝脏的输送，从而加剧脂肪性肝病。重要的是，产生过多皮质醇或服用大剂量类固醇激素的患者会出现许多此类并发症，包括肥胖和脂肪肝。我们将使用从肝脏和脂肪培养的细胞来确定皮质醇对脂肪积累的影响。我们还将评估调整生产和分解皮质醇的影响。我们将创建啮齿动物模型，在该模型中，我们已经通过基因操作了产生和分解皮质醇的酶。我们相信，减少皮质醇的产生和促进分解将会有有益的效果。最后，我们将使用减少皮质醇产生的药物进行临床研究，看看它们是否可以减少肝脏内的脂肪堆积。

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.