Brain Apolipoprotein AIV, Food Intake and Obesity

描述（由申请人提供）：载脂蛋白AIV （apo AIV）是肠道细胞在脂质摄食反应中释放的循环信号，它有助于脂质餐的厌食作用。我们已经证明载脂蛋白AIV也在下丘脑合成，并且下丘脑载脂蛋白AIV基因的表达受到生理调控。我们的长期目标是了解下丘脑载脂蛋白AIV在肥胖发展中的作用，以及如何将其调节为预防和治疗目的。本应用程序的目的是评估三个假设。1)下丘脑载脂蛋白AIV功能降低时，食量长期增加，发生肥胖。因此，与瘦肉动物相比，肥胖动物下丘脑载脂蛋白AIV水平和/或下丘脑载脂蛋白AIV对饲料脂质的反应较低。2)外周载脂蛋白AIV在穿越血脑屏障（BBB）后参与了载脂蛋白AIV的中枢作用。因此，在肥胖动物中，血脑屏障运输受损可能导致下丘脑载脂蛋白AIV水平和活性降低。3)下丘脑载脂蛋白AIV与其他调节神经肽相互作用，发挥其生理功能。我们将从以下三个方面对这些假设进行评估：1)确定几种肥胖和瘦肉动物下丘脑载脂蛋白AIV基因表达和蛋白水平，以及下丘脑载脂蛋白AIV对饲料脂质的反应。我们将进一步确定载脂蛋白AIV敲除小鼠对慢性高脂肪喂养的反应。2)表征载脂蛋白AIV从血液进入中枢神经系统（CNS）的运输，并评估由中央或静脉给药的载脂蛋白AIV激活的脑区。3)确定载脂蛋白AIV与下丘脑内其他调节肽的相互作用。拟议的工作具有创新性，因为它解决了重要的未解问题。此外，本研究利用了实验方法的可用性和几种独特的动物模型。最后，该研究的结果将具有重要意义，因为预计这些研究将有助于更广泛地了解载脂蛋白AIV在调节能量稳态中的作用。这一新知识可能会导致预防和治疗干预的新目标，这对这个国家越来越多的肥胖者尤其重要。

DESCRIPTION (provided by applicant): Apolipoprotein AIV (apo AIV) is a circulating signal released from intestinal cells in response to lipid feeding, and it contributes to the anorectic effect of a lipid meal. We have demonstrated that apo AIV is also synthesized in the hypothalamus, and that hypothalamic apo AIV gene expression is regulated physiologically. Our long-range goal is to understand the role of hypothalamic apo AIV in the development of obesity and how it can be modulated for preventive and therapeutic purposes. The objective of this application is to evaluate three hypotheses. 1) When hypothalamic apo AIV function is reduced, meal size is chronically increased and obesity develops. Obese animals will, therefore, have lower hypothalamic apo AIV levels and/or lower responsivity of hypothalamic apo AIV to dietary lipids relative to lean animals. 2) Peripheral apo AIV contributes to the central action of apo AIV after crossing the blood-brain barrier (BBB). Therefore, impaired transport across the BBB may result in reduced hypothalamic apo AIV levels and action in obese animals. 3) Hypothalamic apo AIV interacts with other regulatory neuropeptides to exert its physiological function. These hypotheses will be evaluated with the following three specific aims: 1) To determine hypothalamic apo AIV gene expression and protein levels and the responsivity of hypothalamic apo AIV to dietary lipids in several strains of obese and lean animals. We will further determine the response to chronic high-fat feeding in apo AIV knockout mice. 2) To characterize the transport of apo AIV from blood into the central nervous system (CNS) and to assess the areas in the brain that are activated by apo AIV administered either centrally or intravenously. 3) To determine the interaction of apo AIV with other regulatory peptides within the hypothalamus. The proposed work is innovative because it addresses important unanswered questions. In addition, the proposed research takes advantage of the availability of experimental methods and several unique animal models. Finally, the outcomes of the research will be significant because it is expected that these studies will contribute to broader understanding of the role of apo AIV in the regulation of energy homeostasis. This new knowledge may lead to novel targets for preventive and therapeutic interventions that will be particularly important to the growing numbers of obese persons in this country.