Regulation of Food Intake and Body Weight by Brain Apo E

载脂蛋白E（apoE）在肝脏和大脑中大量产生。它扮演着重要的角色， 脂质的代谢和再分布。在大脑中，apoE与发育，再生， 和神经保护。最近，我们发现了apoE的一种新功能，即中枢给药apoE 有效抑制食物摄入和体重，而不会引起毒性迹象，并阻断 内源性脑apoE及其特异性抗体增加食物摄入。具有靶向缺失的小鼠 apoE基因小鼠比野生型小鼠消耗更多的食物和体重。这些结果表明，apoE发挥作用， 在控制食物摄入量和体重方面发挥重要作用。因此，我们推测，apoE不足 生产可能使动物易患肥胖症。我们的长期目标是确定 作为预防和治疗肥胖的手段，本发明提供了用于抑制食欲的药理学靶点。的 本具体应用的目的是鉴定介导apoE在控制 食物摄入量和体重。第一个具体目标将评估增加食物的假设 肥胖动物的消耗部分是由于下丘脑（一个中心区域）中apoE信号的减少 调节能量平衡第二个具体目标将评估下丘脑 apoE通过影响分解代谢调节神经肽和/或其受体发挥其厌食功能。 第三个具体目标是通过确定apoE的抑制食欲作用， apoE相关受体和信号转导途径。这项工作是创新的，因为它 评估了apoE在脑中的一种新的生理功能。此外，它还利用富人 辛辛那提大学肥胖和脂质研究中心的研究环境， 现有的实验方法和几种独特的动物模型。此外，这项研究的结果 将对肥胖研究领域产生积极影响，因为基本的新知识是 预计将促进制定预防和治疗干预措施， 肥胖，从而降低美国的医疗保健费用。

Apolipoprotein E (apoE) is produced abundantly in the liver and brain. It plays important roles in the metabolism and redistribution of lipids. In the brain, apoE has been implicated in development, regeneration, and neuroprotection. Recently, we have identified a novel function of apoE, i.e. centrally administered apoE potently suppresses food intake and body weight without eliciting signs of toxicity, and blocking the action of endogenous brain apoE with its specific antibody increases food intake. Mice with a targeted deletion of the apoE gene consume more food and weigh more than wild-type mice. These results imply that apoE plays an essential role in the control of food intake and body weight. Thus, we speculate that insufficient apoE production may render an animal vulnerable to the development of obesity. Our long-term goal is to identify pharmacological targets for suppressing appetite as a means of preventing and treating obesity. The objective of this specific application is to identify the mechanism(s) mediating apoE's effect in the control of food intake and body weight. The first specific aim will assess the hypothesis that increased food consumption in obese animals is due in part to reduced apoE signaling in the hypothalamus, a central area regulating energy homeostasis. The second specific aim will evaluate the hypothesis that hypothalamic apoE exerts its anorectic function by influencing catabolic regulatory neuropeptides and/or their receptors. The third specific aim will identify the mechanisms that mediate apoE's anorectic action by determining apoE-relevant receptor(s) and signal transduction pathways. The proposed work is innovative because it assesses a novel physiological function of apoE in the brain. In addition, it takes advantage of the rich research environment in the University of Cincinnati Obesity and Lipid Research Centers and employs available experimental methods and several unique animal models. Moreover, outcomes of this research will have a positive impact on the field of obesity research because the fundamental new knowledge is expected to facilitate the development of preventive and therapeutic interventions to address the epidemic of obesity and, consequently, to decrease health care costs in the United States.