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

环境与肥胖：用金雀异黄素预防应激激素引起的肥胖

• 批准号: 7090949
• 负责人: NICK LU
• 金额: $ 10.8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090949
• 关键词: Address; Adipose tissue; Anti-Obesity Agents; Behavior; Body Weight; Body fat; Brain; Cardiovascular system; Corticosterone; Deposition; Development; Diet; Dyslipidemias; Eating; Elevation; Endocrine; Endocrine disruption; Environment; Environmental Estrogen; Environmental Exposure; Estrogens; Fatty acid glycerol esters; Food; Food Intake Regulation; Gene Expression; Gene Targeting; Genes; Genistein; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Homeostasis; Hormones; Hyperphagia; Hypothalamic structure; Isoflavones; Metabolic; Metabolic Control; Microarray Analysis; Molecular; Molecular Target; Mus; Obesity; Organ; Outcome; Pattern; Physiological; Pituitary-Adrenal System; Plasma; Polymerase Chain Reaction; Property; Public Health; Regulation; Regulator Genes; Reporting; Research; Research Personnel; Rodent; Rodent Model; Role; Signaling Molecule; Source; Stress; System; Testing; Time; Tissues; Treatment Protocols; base; blood lipid; environmental agent; environmental stressor; improved; insight; interest; multidisciplinary; novel; novel therapeutics; obesity prevention; prevent; programs; reproductive; response; success

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.

描述（由申请人提供） 对环境压力源的生理反应会升高血浆应激激素，包括糖皮质激素，众所周知，糖皮质激素会导致肥胖。 我们的长期目标是预防因环境暴露引起的肥胖。 金雀异黄酮是一种在食物中发现的类似环境雌激素的化合物，已被证明具有抗肥胖特性。 然而，金雀异黄素是否可以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。 候选人假设金雀异黄素可以预防啮齿动物模型中糖皮质激素引起的肥胖。 为了检验这一假设，将在两个关键代谢器官：脂肪组织和大脑中鉴定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被确定。此外，候选人还将研究金雀异黄酮是否可以抵消糖皮质激素在代谢基因网络、食物摄入和体内脂肪增加方面的不利作用。 为了实现这些目标，小鼠将接受媒介物、皮质酮（一种内源性糖皮质激素）、金雀异黄酮或皮质酮加金雀异黄酮的治疗。将进行微阵列分析，以确定每种治疗对下丘脑和脂肪组织基因网络的调节作用。此外，还将确定每次治疗对食物摄入、血脂、体重和体脂的调节。 具体目标 1 将定义糖皮质激素引起的代谢基因网络和肥胖的变化。 具体目标 2 将定义金雀异黄素引起的代谢基因网络和肥胖的变化。 具体目标 3 将确定金雀异黄酮在对抗糖皮质激素引起的肥胖中的作用。 候选人预计金雀异黄素将抵消糖皮质激素引起的代谢基因网络变化，从而产生积极的生理结果。 与单独使用皮质酮治疗相比，金雀异黄素加皮质酮治疗预计会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）。 代表性基因的调控也将使用实时 PCR、放射免疫组织化学或定量放射自显影分析进行单独验证。 该提案的研究结果将增进对两种环境相关因子（即应激激素和染料木黄酮）及其在调节能量稳态和体重的多级系统中的作用的理解。 这些研究将提供一个框架来揭示应激激素引起的肥胖的分子基础及其潜在的治疗方法。