Brain Apolipoprotein AIV, Food Intake and Obesity

超出提供的空间。载脂蛋白AIV(Apo AIV)是肠道细胞对脂肪摄取的反应而释放的一种循环信号，参与了脂肪餐的厌食作用。我们已经证明apo AIV也是在下丘脑合成的，并且下丘脑apo AIV基因的表达受到生理调节。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，以及它如何被调节以达到预防和治疗的目的。这个应用程序的目标是评估三个假设。1)当下丘脑apo AIV功能降低时，进食量会慢性增加，从而导致肥胖。因此，肥胖动物的下丘脑载脂蛋白AIV水平和/或下丘脑载脂蛋白AIV对饮食脂质的响应性比瘦小动物低。2)外周ApoAIV通过血脑屏障(BBB)参与ApoAIV的中枢作用。因此，跨血脑屏障转运受损可能导致肥胖动物下丘脑载脂蛋白AIV水平和作用的降低。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。这些假说将通过以下三个具体目标进行评估：1)确定几个品系的肥胖和瘦肉动物下丘脑apo AIV的基因表达和蛋白水平，以及下丘脑apo AIV对饮食脂质的响应。我们将进一步确定载脂蛋白AIV基因敲除小鼠对长期高脂喂养的反应。2)研究载脂蛋白AIV从血液到中枢神经系统(CNS)的转运过程，并对中枢或静脉注射载脂蛋白AIV激活的脑区进行评估。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悬而未决的问题。此外，拟议的研究还利用了现有的实验方法和几种独特的动物模型。最后，这项研究的结果将是重要的，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。这一新知识可能导致预防和治疗干预措施的新目标，这对该国日益增长的肥胖者尤为重要。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================