The Role of 11beta-HSD1 in Type II Diabetes and Obesity

描述(由申请人提供)： 众所周知，皮质醇过多的患者会患上库欣综合征，并伴有中心性肥胖和胰岛素抵抗。然而，最近对人类和啮齿动物的研究表明，组织而不是血浆皮质醇过量在特发性肥胖和代谢综合征的发展中起到了作用，这种作用是通过细胞内类固醇将惰性循环皮质酮(啮齿动物的11-脱氢皮质酮)重新激活为活性皮质醇(皮质酮)，这种酶被称为11β-羟基类固醇脱氢酶1(11β-HSD1)。为了支持这一点，脂肪和肝脏细胞中这种酶过量的小鼠通过增加细胞内活性皮质醇水平而出现胰岛素抵抗和代谢综合征。同样，我们使用了一种名为肥胖db/db小鼠的2型糖尿病动物模型，发现它们的肝脏和脂肪中11β-HSD1水平较高，这与它们的胰岛素抵抗、高血糖和肥胖呈正相关。我们和其他人还报道，抑制这种酶可以增加肥胖小鼠和人类的胰岛素敏感性。我们假设酶11β-HSD1决定细胞内类固醇的可获得性和胰岛素敏感性，进一步，11β-HSD1可能成为治疗2型糖尿病和肥胖症的新靶点。我们现在感兴趣的是试图了解为什么细胞内糖皮质激素供应增加可能导致胰岛素抵抗和肥胖，以及旨在降低这种酶组织水平的内源性操作和外源性药物是否会改善肥胖啮齿动物的2型糖尿病和肥胖症。在这项拨款申请中，我们将通过用11β-HSD1抑制剂调节11β-HSD1的活性和特异性siRNA沉默(针对11β-HSD1的表达)，研究细胞内糖皮质激素的可用性对小鼠肝细胞和脂肪细胞原代培养中胰岛素信号和葡萄糖运输的影响。动物研究将进一步确定通过病毒介导的siRNA技术对11β-HSD1进行内源性调节和特异性抑制，从而降低组织中糖皮质激素在胰岛素敏感性和体重方面的可用性的好处。我们的实验将有助于全面阐明肝脏和脂肪组织内选择性酶抑制作为一种治疗代谢综合征的新策略的潜在有益机制，从而为开发可用于治疗人类2型糖尿病和/或肥胖症的特异性11β-HSD1抑制剂奠定基础。

DESCRIPTION (provided by applicant): 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.