Environment and Obesity: preventing stress hormone-induced obesity with genistein

描述(由申请人提供) 对环境应激源的生理反应会增加包括糖皮质激素在内的血浆应激激素，糖皮质激素是众所周知的导致肥胖的因素。我们的长期目标是防止因环境暴露而导致的肥胖。金雀异黄素是一种在食物来源中发现的环境雌激素样化合物，已被证明具有抗肥胖特性。然而，金雀异黄素是否能抵消糖皮质激素对代谢基因、食物摄取行为和脂肪沉积的有害影响尚不清楚。候选人假设金雀异黄素可以在啮齿动物模型中预防糖皮质激素诱导的肥胖。为了验证这一假设，将在两个关键的代谢器官：脂肪组织和大脑中识别与糖皮质激素诱导的肥胖有关的基因。同样，金雀异黄素在这两个代谢控制中心的基因调控作用也将得到确定。此外，候选人将研究金雀异黄素是否能抵消糖皮质激素在代谢基因网络、食物摄入和体内脂肪积累中的不利作用。为了实现这些目标，小鼠将接受赋形剂、皮质酮(一种内源性糖皮质激素)、金雀异黄素或皮质酮加金雀异黄素治疗。将进行微阵列分析，以确定每种治疗方法对下丘脑和脂肪组织中基因网络的调节作用。此外，还将确定每个治疗对食物摄入量、血脂水平、体重和体脂的调节。具体目标1将定义糖皮质激素诱导的代谢基因网络的变化和肥胖。具体目标2将定义染料木素诱导的代谢基因网络的变化和肥胖症。具体目标3将确定金雀异黄素在对抗糖皮质激素诱导的肥胖中的作用。候选人预计金雀异黄素将抵消糖皮质激素诱导的代谢基因网络的变化，这反过来将产生积极的生理结果。与皮质酮单独治疗相比，染料木素联合皮质酮治疗有望产生改善代谢基因表达模式和包括体重在内的有利代谢参数。代表性基因的调控也将使用实时聚合酶链式反应、放射免疫组织化学或定量放射自显影分析来单独验证。这一建议的发现将加深对两种环境相关物质，即应激激素和染料木素的理解，以及它们在调节能量稳态和体重的多水平系统中的作用。这些研究将提供一个框架，以揭示应激激素诱导肥胖的分子基础及其潜在的治疗方法。

DESCRIPTION (provided by applicant) Physiological responses to environmental stressors elevate plasma stress hormones including glucocorticoids, which are well known to cause obesity. Our long-term goal is to prevent obesity caused by environmental exposures. Genistein, an environmental estrogen-like compound found in food sources, has been demonstrated to have anti-obesity properties. However, whether genistein counteracts the deleterious effects of glucocorticoids on metabolic genes, food intake behavior, and fat deposition is not known. The candidate hypothesizes that genistein may prevent glucocorticoid-induced obesity in a rodent model. To test this hypothesis, genes involved in glucocorticoid-induced obesity will be identified in two key metabolic organs: adipose tissue and brain. Similarly, the gene regulatory effects of genistein in these two metabolic control centers will also be determined. In addition, the candidate will investigate whether genistein counteracts the adverse actions of glucocorticoids in metabolic gene networks, food intake, and body fat accretion. To achieve these goals, mice will be treated with vehicle, corticosterone (an endogenous glucocorticoid), genistein, or corticosterone plus genistein. Microarray analysis will be performed to define the regulatory effects of each treatment on gene networks in the hypothalamus and in adipose tissue. In addition, regulation of food intake, blood lipid profiles, body weight, and body fat by each treatment will also be determined. Specific Aim 1 will define glucocorticoid-induced changes in metabolic gene networks and adiposity. Specific Aim 2 will define genistein-induced changes in metabolic gene networks and adiposity. Specific Aim 3 will determine the role of genistein in counteracting glucocorticoid-induced obesity. The candidate anticipates that genistein will counteract glucocorticoid-induced changes in metabolic gene networks, which in turn will result in positive physiological outcomes. Genistein plus corticosterone, compared to corticosterone alone treatment, is expected to yield improved metabolic gene expression patterns and favorable metabolic parameters including body weight. The regulation of representative genes will also be individually verified using real time PCR, radioimmunohistochemistry, or quantitative autoradiographical analysis. The findings of this proposal will improve the understanding of two environmental-related agents, i.e., stress hormones and genistein, and their actions in the multi-level systems regulating energy homeostasis and body weight. These studies will provide a framework to uncover the molecular basis underlying stress hormone-induced obesity and its potential treatment.