Regulation of Food Intake and Body Weight by Brain Apo E

描述（由申请人提供）：载脂蛋白E（apoE）在肝脏和大脑中大量产生。它在脂质的代谢和再分配中起重要作用。在大脑中，apoE与发育、再生和神经保护有关。最近，我们发现了apoE的一种新功能，即中枢给药apoE可有效抑制食物摄入和体重，而不会引起毒性体征，并且用其特异性抗体阻断内源性脑apoE的作用可增加食物摄入。与野生型小鼠相比，有针对性地删除apoE基因的小鼠消耗更多的食物，体重也更重。这些结果表明，apoE在控制食物摄入和体重方面起着重要作用。因此，我们推测，apoE生产不足可能会使动物易受肥胖症的发展。我们的长期目标是确定抑制食欲的药理学靶点，作为预防和治疗肥胖的一种手段。该具体应用的目的是鉴定介导apoE在控制食物摄入和体重中的作用的机制。第一个具体目标将评估肥胖动物食物消耗增加部分是由于下丘脑（调节能量稳态的中心区域）apoE信号减少的假设。第二个具体的目标将评估的假设，下丘脑apoE发挥其厌食功能的影响分解代谢调节神经肽和/或其受体。第三个具体目标是通过确定apoE相关受体和信号转导途径来确定介导apoE减食欲作用的机制。这项工作是创新的，因为它评估了apoE在大脑中的一种新的生理功能。此外，它还利用了辛辛那提大学肥胖和脂质研究中心丰富的研究环境，并采用了可用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，因为基本的新知识有望促进预防和治疗干预措施的发展，以解决肥胖症的流行，从而降低美国的医疗保健费用。

DESCRIPTION (provided by applicant): 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.