Regulation of Food Intake and Body Weight by Brain Apo E

大脑 Apo E 对食物摄入量和体重的调节

基本信息

批准号：
7337061
负责人：
Min Liu
金额：
$ 28.21万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7337061
关键词：
Address Affect Amino Acids Animal Model Animals Antibodies Apolipoprotein E Appetite Depressants Appetitive Behavior Area Behavioral Biochemical Blocking Antibodies Body Weight Brain Cardiovascular Diseases Consumption Data Desire for food Development Eating Energy Metabolism Environment Epidemic Equilibrium Equipment Etiology Faculty Feeding behaviors Food Food Intake Regulation Genes Goals Health Health Care Costs Homeostasis Hypothalamic structure Individual Investigation Knockout Mice Knowledge LDL-Receptor Related Protein 1 Leptin Lipids Lipoproteins Liver Malaise Measures Mediating Metabolism Methods Molecular Mus Natural regeneration Neuraxis Neuropeptides Neurosciences Obesity Outcome Outcome Study Outcomes Research Pathway interactions Peripheral Physiological Play Positioning Attribute Preventive Principal Investigator Production Protein Biosynthesis Proteins Publishing Range Rattus Receptor Signaling Reporting Research Research Personnel Resources Risk Factors Role Satiation Signal Transduction Signal Transduction Pathway System Therapeutic Intervention Tissues Toxic effect United States Universities Water consumption Weight maintenance regimen Wild Type Mouse Work base cholesterol transporters diabetes risk field study food consumption innovation insight knockout gene lipid transport member neuroprotection novel obesity prevention prevent programs receptor

项目摘要

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.

载脂蛋白 E (apoE) 在肝脏和大脑中大量产生。它在其中发挥着重要作用脂质的代谢和重新分配。在大脑中，apoE 与发育、再生、和神经保护。最近，我们发现了apoE的一个新功能，即中枢管理的apoE 有效抑制食物摄入和体重，而不引起毒性迹象，并阻止内源性脑apoE及其特异性抗体可增加食物摄入量。具有针对性删除的小鼠 apoE基因比野生型小鼠消耗更多的食物并且体重更重。这些结果表明 apoE 发挥作用在控制食物摄入和体重方面发挥着重要作用。因此，我们推测apoE不足生产可能会使动物容易患上肥胖症。我们的长期目标是确定抑制食欲作为预防和治疗肥胖的一种手段的药理学目标。这该特定应用的目的是确定介导 apoE 在控制中的作用的机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）的 apoE 信号减少所致调节能量稳态。第二个具体目标将评估下丘脑的假设 apoE 通过影响分解代谢调节神经肽和/或其受体来发挥其厌食功能。第三个具体目标将通过确定介导 apoE 的厌食作用的机制 apoE 相关受体和信号转导途径。拟议的工作具有创新性，因为它评估 apoE 在大脑中的新生理功能。另外，它还利用了丰富的资源辛辛那提大学肥胖和脂质研究中心的研究环境和雇员可用的实验方法和几种独特的动物模型。此外，这项研究的成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，以应对流行病肥胖，从而降低美国的医疗保健成本。