Brain apoA-IV Mediates Estrogenic Reduction of Dietary Obesity in Female Rats

描述（由申请人提供）：在理解雌激素在许多物种（包括人类）中有效抑制食物摄入和减轻体重的机制方面存在根本性差距。这一差距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作为雌激素信号传导受损的女性肥胖预防和治疗的手段。令人信服的证据表明，E2通过间接机制发挥其促孕作用;即，E2增加了其他生理信号的强度，减少了膳食量。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，并确定这种作用如何在雌性大鼠中因慢性高脂饮食（HFD）消耗而受损。中心假设是E2通常刺激NTS中的apoA-IV基因表达，并且这种作用被HFD的慢性消耗所削弱，导致食物摄入增加和饮食性肥胖的发展。这一假设是基于我们在HFD诱导的肥胖卵巢切除（OVX）大鼠的初步数据。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的这种作用如何通过长期食用HFD而改变，雌激素信号传导的关键成分就可以被操纵，从而产生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，我们提出通过追求三个具体目标来检验这一假设。首先，鉴定雌激素受体和介导E2对apoA-IV基因表达影响的DNA反应元件。其次，确定E2对apoA-IV基因表达的降低作用是否有助于饮食性肥胖的发展，以及是否可以通过apoA-IV的施用来规避。第三，探讨HFD诱导的肥胖雌性大鼠雌激素信号通路受损的机制。这项研究是创新的，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。这种方法代表了对现状的实质性偏离，并且预期将导致女性肥胖症的有效治疗。这一应用是重要的，因为它预计将促进了解雌激素如何调节正常雌性大鼠的能量稳态，以及当动物被喂食HF饮食时，这种效果如何受损。最终，这些知识将促进预防和治疗干预措施的发展，以解决肥胖症的流行，从而提高许多受影响的个人的生活质量，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.