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

描述(申请人提供)：在包括人类在内的许多物种中，雌激素有效抑制食物摄取和减轻体重的机制(S)的理解存在根本差距。这一差距代表着一个重要的问题，因为除非它被弥合，否则雌激素中介和途径不太可能成为雌激素信号受损的女性肥胖预防和治疗的一种手段。令人信服的证据表明，E2通过一种间接机制发挥其厌食作用；即，E2增加了其他减少膳食的生理信号的强度。载脂蛋白A-IV(apoA-IV)是一种重要的饱和因子，在这方面是一个引人注目的候选者。本研究的目的是确定E2刺激NTS载脂蛋白A-IV基因表达的机制，并确定长期高脂饮食(HFD)对雌性大鼠这一效应的影响。核心假设是，E2通常会刺激NTS中apoA-IV基因的表达，这种作用会因长期摄入高脂饮食而减弱，从而导致食物摄入量增加和饮食肥胖的发生。这一假设是基于我们在HFD诱导的肥胖卵巢切除(OVX)大鼠中的初步数据。这项拟议研究的基本原理是，一旦了解了雌激素如何刺激载脂蛋白A-IV基因表达的特定机制以及长期摄入高脂饮食如何改变E2的这种影响，就可以从药理学上操纵雌激素信号的关键成分(S)，从而为预防和治疗女性饮食肥胖带来创新的靶点。在强劲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说。首先，确定雌激素受体和DNA反应元件介导E2‘S对载脂蛋白A-IV基因表达的影响。第二，确定E_2‘S降低载脂蛋白A-IV基因表达的影响是否参与了饮食性肥胖的发生，以及是否可以通过给予载脂蛋白A-IV来避免这种情况。第三，探讨高脂饮食诱导肥胖雌性大鼠雌激素信号转导受损的机制。这项拟议的研究具有创新性，因为它将基础研究发现转化为临床前模型，旨在确定新的治疗靶点。这种方法与现状有很大的不同，有望为女性肥胖症提供有效的治疗方法。这一应用具有重要意义，因为它有望促进理解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HF饮食时，这种影响是如何受损的。归根结底，这些知识将有助于开发预防和治疗干预措施，以应对肥胖症的流行，从而改善许多患有肥胖症的人的生活质量，并降低美国的医疗保健成本。 公共卫生相关性：这项建议的目的是确定雌激素刺激脑内载脂蛋白A-IV基因表达的机制(S)，并确定这一作用在长期喂养高脂饮食的雌性大鼠中是如何受损的。因此，拟议的研究与NIH任务的一部分有关，该部分涉及发展基础知识，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。

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.