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升高血浆应激激素，包括糖皮质激素，这是众所周知的导致肥胖。 我们的长期目标是防止环境暴露导致的肥胖。 染料木黄酮是一种在食物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，染料木黄酮是否抵消糖皮质激素对代谢基因、食物摄入行为和脂肪沉积的有害影响尚不清楚。 该候选人假设染料木黄酮可以预防啮齿动物模型中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：脂肪组织和大脑中鉴定糖皮质激素诱导的肥胖症相关基因。 同样，染料木黄酮在这两个代谢控制中心的基因调控作用也将被确定。此外，候选人将研究染料木黄酮是否抵消糖皮质激素在代谢基因网络，食物摄入和身体脂肪堆积中的不利作用。 为了实现这些目标，将用媒介物、皮质酮（内源性糖皮质激素）、染料木黄酮或皮质酮加染料木黄酮处理小鼠。将进行微阵列分析，以确定每种治疗对下丘脑和脂肪组织中基因网络的调节作用。此外，还将确定每种治疗对摄食量、血脂谱、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和肥胖的变化。 具体目标2将定义染料木黄酮诱导的代谢基因网络和肥胖的变化。 具体目标3将确定染料木黄酮在抵消糖皮质激素诱导的肥胖中的作用。 候选人预计，染料木黄酮将抵消糖皮质激素诱导的代谢基因网络的变化，这反过来又会导致积极的生理结果。 与单独的皮质酮治疗相比，染料木黄酮加皮质酮预期产生改善的代谢基因表达模式和有利的代谢参数，包括体重。 还将使用真实的时间PCR、放射免疫组织化学或定量放射自显影分析单独验证代表性基因的调控。 本提案的研究结果将增进对两种与环境有关的物质的了解，即：应激激素和染料木黄酮，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，以揭示潜在的应激性肥胖及其潜在的治疗的分子基础。

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.