Brain apoA-IV mediates estrogenic reduction of dietary obesity in female rats

脑apoA-IV介导雌性大鼠雌激素减少饮食肥胖

• 批准号: 8163309
• 负责人: Min Liu
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-22 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8163309
• 关键词: Address; Agonist; Animal Feed; Attenuated; Basic Science; Behavioral; Binding; Biological; Biological Assay; Body Weight; Brain; Brain Stem; Chromatin; Chronic; Complex; Consumption; DNA; DNA Methylation; Data; Development; Diet; Eating; Epidemic; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Etiology; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Gene Expression; Genes; Genetic Transcription; Health Care Costs; Homeostasis; Human; Hyperphagia; Individual; Knockout Mice; Knowledge; Luciferases; Maintenance; Mediating; Mediator of activation protein; Menopause; Messenger RNA; Mission; Nucleus solitarius; Obesity; Outcome; Pathway interactions; Physiological; Pre-Clinical Model; Precipitation; Prevention; Preventive Intervention; Public Health; Quality of life; Rattus; Relative (related person); Research; Response Elements; Risk Factors; Satiation; Signal Transduction; Staging; Testing; Therapeutic Intervention; Translating; United States; Ventricular; Weight; Woman; Work; apolipoprotein A-IV; base; feeding; food consumption; improved; innovation; mRNA Expression; model design; novel; obesity prevention; obesity treatment; prevent; promoter; response

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding the mechanism(s) by which estrogens potently inhibit food intake and reduce body weight in many species, including humans. This gap represents an important problem because unless it is closed, it is unlikely that estrogenic intermediaries and pathways can be targeted as a means of obesity prevention and treatment in women with impaired estrogen signaling. Compelling evidence suggests that E2 exerts its anorexigenic action through an indirect mechanism; i.e., that E2 increases the strength of other physiological signals that reduce meal size. Apolipoprotein A-IV (apoA-IV), an important satiation factor, is a compelling candidate in this regard. The objective of this proposal is to identify the mechanisms through which E2 stimulates apoA-IV gene expression in the NTS and to determine how this effect becomes impaired in female rats by chronic high-fat diet (HFD) consumption. The central hypothesis is that E2 normally stimulates apoA-IV gene expression in the NTS and that this effect is impaired by chronic consumption of a HFD, leading to increased food intake and the development of dietary obesity. This hypothesis is based on our preliminary data in HFD-induced obese ovariectomized (OVX) rats. The rationale for the proposed research is that once the particular mechanisms as to how E2 stimulates apoA-IV gene expression and how such effect of E2 is altered by chronic consumption of a HFD are understood, the key component(s) of estrogen signaling could be manipulated pharmacologically, leading to innovative targets to the prevention and treatment of dietary obesity in women. Guided by strong preliminary data, we propose testing this hypothesis by pursuing three specific aims. First, to identify estrogen receptor and DNA response elements that mediate E2's effect on apoA-IV gene expression. Second, to determine whether E2's reduced effect on apoA-IV gene expression contributes to the development of dietary obesity, and whether this can be circumvented by administration of apoA-IV. Third, to determine the mechanism of impaired estrogen signaling in HFD-induced obese female rats. The proposed research is innovative because it translates basic research discovery to a pre-clinical model designed to identify novel treatment targets. This approach represents a substantial departure from the status quo, and is expected to result in an efficacious therapy of obesity in women. This application is significant because it is expected to advance the understanding of how estrogens regulate energy homeostasis in normal female rats, and how such effect is impaired when the animals are fed a HF diet. Ultimately, such knowledge will facilitate the development of preventive and therapeutic interventions to address the epidemic of obesity and, consequently, to improve quality of life for many afflicted individuals and to decrease health care costs in the United States. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to identify the mechanism(s) through which estrogens stimulate apoA-IV gene expression in the brain and to determine how this action is impaired in female rats chronically fed a high-fat diet. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will facilitate the development of preventive and therapeutic interventions to address the epidemic of obesity in the United States.

描述（由申请人提供）：对于雌激素有效抑制食物摄入和减轻许多物种（包括人类）体重的机制的理解存在根本性差距。这个缺口代表了一个重要的问题，因为除非它被关闭，否则雌激素中介体和途径不太可能成为雌激素信号受损女性预防和治疗肥胖的手段。令人信服的证据表明，E2 通过间接机制发挥其抑制食欲的作用。也就是说，E2 会增加其他减少膳食量的生理信号的强度。载脂蛋白 A-IV (apoA-IV) 是一种重要的饱腹感因子，在这方面是一个令人信服的候选者。该提案的目的是确定 E2 刺激 NTS 中 apoA-IV 基因表达的机制，并确定雌性大鼠长期高脂饮食 (HFD) 消耗如何损害这种效应。核心假设是，E2 通常会刺激 NTS 中的 apoA-IV 基因表达，而长期食用 HFD 会削弱这种作用，从而导致食物摄入量增加和饮食性肥胖的发生。这一假设基于我们在 HFD 诱导的肥胖卵巢切除 (OVX) 大鼠中的初步数据。拟议研究的基本原理是，一旦了解了 E2 如何刺激 apoA-IV 基因表达以及 E2 的这种作用如何通过长期食用 HFD 改变的具体机制，雌激素信号传导的关键组成部分可能会被理解。药理学上的操纵，导致了预防和治疗女性饮食性肥胖的创新目标。在强有力的初步数据的指导下，我们建议通过追求三个具体目标来检验这一假设。首先，鉴定介导 E2 对 apoA-IV 基因表达影响的雌激素受体和 DNA 反应元件。其次，确定 E2 对 apoA-IV 基因表达的影响降低是否会导致饮食性肥胖的发生，以及是否可以通过施用 apoA-IV 来避免这种情况。第三，确定HFD诱导的肥胖雌性大鼠雌激素信号受损的机制。拟议的研究具有创新性，因为它将基础研究发现转化为旨在识别新治疗靶点的临床前模型。这种方法与现状有很大的不同，预计将有效治疗女性肥胖。这一应用具有重要意义，因为它有望促进人们对雌激素如何调节正常雌性大鼠的能量稳态，以及当动物喂食高频饮食时这种效应如何受到损害的理解。最终，这些知识将促进预防和治疗干预措施的发展，以解决肥胖的流行问题，从而改善许多患病人群的生活质量，并降低美国的医疗保健费用。 公共健康相关性：本提案的目的是确定雌激素刺激大脑中 apoA-IV 基因表达的机制，并确定长期喂养高脂肪饮食的雌性大鼠如何损害这种作用。因此，拟议的研究与 NIH 使命的一部分相关，该使命涉及发展基础知识，以促进预防和治疗干预措施的发展，以解决美国肥胖症的流行问题。