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）：了解雌激素有效抑制食物摄入并减轻许多物种（包括人类）的体重的机制存在根本的差距。该差距代表了一个重要的问题，因为除非封闭，否则不可能将雌激素中介和途径作为预防肥胖和治疗雌激素信号传导的肥胖症的一种手段。令人信服的证据表明，E2通过间接机制发挥了其厌食性作用。即，E2增加了其他生理信号的强度，从而降低了进餐的大小。载脂蛋白A-IV（ApoA-IV）是一个重要的饱腹因子，在这方面是令人信服的候选者。该提案的目的是确定E2刺激NTS中apoA-IV基因表达的机制，并确定通过慢性高脂饮食（HFD）消耗雌性大鼠在雌性大鼠中如何损害这种作用的机制。中心假设是E2通常刺激NTS中的ApoA-IV基因表达，并且长期消费HFD会损害这种影响，从而导致食物摄入量增加和饮食肥胖的发展。该假设基于我们在HFD诱导的肥胖卵巢切除（OVX）大鼠中的初步数据。拟议的研究的理由是，一旦了解了E2如何刺激APOA-IV基因表达的表达，以及如何通过了解HFD的长期消费来改变E2的这种影响，雌激素信号传导的关键组成部分就可以通过药理学来操纵药理，从而导致创新的饮食和饮食中的妇女治疗。在强大的初步数据的指导下，我们提出通过追求三个特定目标来检验这一假设。首先，鉴定雌激素受体和DNA反应元件，这些元件介导E2对ApoA-IV基因表达的影响。其次，为了确定E2对APOA-IV基因表达的影响是否减少有助于饮食肥胖的发展，以及是否可以通过施用ApoA-IV来规避这。第三，确定HFD诱导的肥胖雌性大鼠中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目标的临床前模型。这种方法代表了与现状的实质性不同，并有望导致女性肥胖症的有效疗法。该应用很重要，因为有望提高对雌激素如何调节正常雌性大鼠能量稳态的理解，以及当动物被喂食HF饮食时，这种影响会受到损害。最终，这种知识将有助于开发预防性和治疗性干预措施，以解决肥胖症的流行，因此，改善许多受苦个人的生活质量并降低美国的医疗保健成本。 公共卫生相关性：该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，并确定在雌性大鼠长期喂养高脂饮食中这种作用如何受损。因此，拟议的研究与NIH使命的一部分有关，即发展基本知识，该知识将有助于开发预防和治疗干预措施，以解决美国肥胖症的流行。