Adipocyte-specific glucocorticoid metabolism: 11betaHSDs

描述(由申请人提供)： 内脏肥胖和代谢综合征是全球公共卫生问题。脂肪组织特异性糖皮质激素代谢的11β-羟基类固醇脱氢酶(11betaHSDs)参与了这些疾病的发病机制。11betaHSD是一种以组织特异性方式催化活性糖皮质激素(GC)和其非活性11-酮代谢产物之间相互转化的酶。类型1亚型(11betaHSD1)激活GC，而类型2亚型(11betaHSD2)失活GC。这项建议的中心目标是确定11betaHSD在涉及能量平衡和体重调节的关键代谢过程中的脂肪细胞特异性GC代谢的作用。目的#1建议建立11betaHSD灭活脂肪细胞特异性GC的转基因小鼠模型。这一目的将通过在小鼠aP2启动子/增强子(aP2-h11betaHSD2)的控制下转基因过表达人11betaHSD2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的和遗传形式的啮齿动物肥胖。这一目标将通过转基因过表达aP2-h11betaHSD2在1)当饲喂高脂肪饮食时对饮食诱导肥胖的敏感性不同的小鼠品系中实现，以及2)成熟的遗传性肥胖模型，如瘦素缺乏的LEPOB/LEPOB小鼠。目的#3探讨瘦素、黑素皮质素和β肾上腺素能通路对11betaHSD1的脂肪细胞特异性调节。 这项建议旨在促进申请者在肥胖和代谢领域的培训和职业发展，特别是在脂肪细胞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、数据演示、导师会议、教学研讨会和科学会议。拟议的研究将在贝丝以色列女执事医学中心的内分泌学、糖尿病和代谢科进行，在那里可以随时获得开展拟议研究的所有资源(设备、技术专长)。最终目标是让申请者成为一名独立的调查员。

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.