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

描述（由申请人提供）：在了解雌激素在包括人类在内的许多物种中有效抑制食物摄入和减轻体重的机制方面存在根本性的差距。这一差距代表了一个重要的问题，因为除非填补这一差距，否则雌激素中介和途径不太可能成为雌激素信号受损妇女预防和治疗肥胖的一种手段。令人信服的证据表明E2通过间接机制发挥其厌氧作用；也就是说，E2增加了其他生理信号的强度，从而减少了进食量。载脂蛋白a - iv （apoA-IV）是一种重要的饱足因子，在这方面是一个令人信服的候选者。本提案的目的是确定E2刺激NTS中apoA-IV基因表达的机制，并确定慢性高脂肪饮食（HFD）消耗对雌性大鼠的影响。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展。这一假设是基于我们在hfd诱导的肥胖去卵巢大鼠（OVX）中的初步数据。这项研究的基本原理是，一旦了解了E2如何刺激apoA-IV基因表达的特定机制，以及E2的这种作用如何被慢性食用HFD改变，就可以从药理学上操纵雌激素信号的关键成分，从而为预防和治疗女性饮食性肥胖找到创新的靶点。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验证这一假设。首先，鉴定雌激素受体和介导E2对apoA-IV基因表达影响的DNA应答元件。第二，确定E2对apoA-IV基因表达的降低是否有助于饮食性肥胖的发生，以及是否可以通过给药apoA-IV来规避这一影响。第三，确定hfd诱导的雌性肥胖大鼠雌激素信号通路受损的机制。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确定新治疗靶点的临床前模型。这种方法与现状有很大的不同，有望成为治疗女性肥胖的有效方法。这一应用具有重要意义，因为它有望促进对雌激素如何调节正常雌性大鼠体内能量稳态的理解，以及当动物被喂食HF饮食时，这种作用是如何受损的。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，从而提高许多受影响个人的生活质量，并降低美国的医疗保健费用。

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.