Adipocyte-specific glucocorticoid metabolism: 11betaHSDs

描述（由申请人提供）： 内脏性肥胖和代谢综合征是全球性的公共卫生问题。脂肪组织特异性糖皮质激素代谢的11 β-羟基类固醇脱氢酶（11 β HSDs）已被牵连在这些疾病的发病机制。11 β HSDs是一种酶，以组织特异性方式催化活性糖皮质激素（GC）与其非活性11-酮代谢物之间的相互转化。1型亚型（11 β HSD 1）激活GC，而2型亚型（11 β HSD 2）使GC失活。该建议的主要目的是确定脂肪细胞特异性GC代谢的作用，通过11 β-HSDs在能量稳态和体重调节中的关键代谢过程。目的#1提出创建通过11 β HSDs使脂肪细胞特异性GC失活的转基因小鼠模型。这一目的将通过在鼠aP 2启动子/增强子（aP 2-h11 β HSD 2）的控制下转基因过表达人11 β HSD 2来实现。目的#2研究脂肪细胞特异性GC失活是否会预防或改善饮食诱导和遗传形式的啮齿动物肥胖。这一目的将通过在1）当喂食高脂肪饮食时对饮食诱导的肥胖症的易感性不同的小鼠品系，和2）良好建立的遗传性肥胖症模型如瘦素缺陷型Lepob/Lepob小鼠中aP 2-h11 β HSD 2的转基因过表达来实现。目的#3探索瘦素、黑皮质素和β肾上腺素能途径对11 β HSD 1的脂肪细胞特异性调节。 该提案旨在促进申请人在肥胖和代谢领域的培训和职业发展，特别是在脂肪细胞的生物学及其对代谢紊乱的贡献方面。职业发展计划包括主要研究项目、实验室技术培训、实验室会议、数据展示、导师会议、教学研讨会和科学会议。拟议的研究将在Beth Israel Deaconess Medical Center的内分泌、糖尿病和代谢科进行，该中心可随时获得开展拟议研究的所有资源（设备、技术专长）。最终目标是让申请人成为独立的调查员。

DESCRIPTION (provided by applicant): Visceral obesity and the metabolic syndrome are global public health problems. Adipose tissue-specific glucocorticoid metabolism by 11beta-hydroxysteroid dehydrogenases (11betaHSDs) has been implicated in the pathogenesis of these disorders. 11betaHSDs are enzymes that catalyze the inter-conversion between active glucocorticoids (GCs) and their inactive 11-keto metabolites in a tissue-specific manner. The type 1 isoform (11betaHSD1) activates GCs while the type 2 isoform (11betaHSD2) inactivates GCs. The central aim of this proposal is to determine the role of adipocyte-specific GC metabolism by 11betaHSDs in key metabolic processes involved in energy homeostasis and the regulation of body weight. Aim #1 proposes to create a transgenic mouse model of adipocyte-specific GC inactivation by 11betaHSDs. This aim will be accomplished through transgenic overexpression of human 11betaHSD2 under the control of the murine aP2 promoter/enhancer (aP2-h11betaHSD2). Aim #2 investigates whether adipocyte-specific GC inactivation will prevent or ameliorate diet-induced and genetic forms of rodent obesity. This aim will be accomplished through transgenic overexpression of aP2-h11betaHSD2 in 1) mouse strains differing in susceptibility to diet-induced obesity when fed a high fat diet, and 2) well-established models of genetic obesity such as leptin-deficient Lepob/Lepob mice. Aim #3 explores the adipocyte-specific regulation of 11betaHSD1 by leptin, melanocortin, and beta adrenergic pathways. This proposal is designed to facilitate the training and career development of the applicant in the field of obesity and metabolism, specifically in the biology of adipocytes and their contribution to metabolic disorders. The career development plan includes the main research project, laboratory technique training, laboratory meetings, data presentations, mentor meetings, didactic seminars, and scientific meetings. The proposed research will take place in the Division of Endocrinology, Diabetes, and Metabolism at Beth Israel Deaconess Medical Center where all the resources (equipment, technical expertise) to carry out the proposed research are readily available. The ultimate goal is for the applicant to become an independent investigator.