NEUROPEPTIDE Y--EFFECTS ON ENERGY METABOLISM

这一建议的重点是可能的中央控制器的 能量代谢可能存在，一个控制器，不仅影响 食物摄入，但提供补充调节能量代谢， 好. 例如，这种中央机制将产生积极的 能量平衡（和肥胖）通过同时增加食物摄入， 减少产热和增加白色脂肪中的能量储存。 我们 研究了对棕色和白色脂肪活性的影响， 脑室内注射NPY，增加食物摄入， 显着抑制产热活动的棕色脂肪，大大 白色脂肪中脂蛋白脂酶活性增加（提示 增加热量储存）。 进一步的研究表明， NPY的代谢作用独立于食物消耗， 同样的方式，当食物摄入量与对照动物或甚至当没有 允许进食。 其他证据表明，长期 施用NPY确实增加了体重增加的效率 每卡路里消耗量。 进一步的研究表明，给予PVN的NPY 降低解偶联蛋白基因的棕色脂肪表达。 我们 因此，建议研究NPY对摄食和代谢的影响， 了解中枢神经系统能量平衡调节的模型系统。 NPY模型的优点是可靠性，效力，正常情况下的测试 动物，在各种营养和环境下测试 环境和中枢神经系统定位的潜力 效果系统。 作为能量代谢的指标，我们计划 测量食物能量摄入，全身能量消耗， 量热法、体重和成分测量、兼性 通过GDP结合在棕色脂肪中的产热和通过 解偶联蛋白和解偶联蛋白mRNA水平的测量，以及 脂蛋白脂酶活性测定白色脂肪活性。 具体问题：（l）剂量反应和时间过程是什么？ NPY对能量代谢的影响我们将测试NPY对 在三个刺激持续时间和几个 设计用于控制饮食影响的对照组类型， 饥饿(2)NPY诱导的摄食变化的作用位点是什么 和新陈代谢，是否有一些位点只有一些效应是 看见了吗？已知NPY在几个下丘脑部位具有一些作用。 NPY对代谢的作用位点尚不清楚。 是各种 在一个或多个地点产生的影响？(3)神经肽Y的作用 对摄食和代谢的影响与饮食成分无关？我们将 确定饮食的常量营养素组成是否影响 喂养和代谢反应的NPY。(4)进食和代谢 NPY产生的变化独立于基线身体能量储存？我们 会通过高脂肪饮食诱导消费而产生肥胖， 通过限制食物摄入量来产生体重不足的大鼠，然后评估 对NPY诱导的摄食和代谢变化的影响。(5)NPY是否会产生 在VMH和LH损伤的动物中也有同样的效果？

This proposal focuses on the possibility that a central controller of energy metabolism might exist, a controller which influences not only food intake but provides complementary regulation of energy metabolism as well. Such a central mechanism would, for example produce positive energy balance (and obesity) by simultaneously increasing food intake, decreasing thermogenesis, and increasing energy storage in white fat. We studied the effects on brown and white fat activity produced by intracerebroventricular injection of NPY, which increased food intake, significantly depressed thermogenic activity in brown fat and greatly increased lipoprotein lipase activity in white fat (suggesting augmentation of caloric storage). Further work indicates that these metabolic effects of NPY are independent of food consumption occurring in the same way when food intake is yoked to control animals or even when no food intake is allowed. Evidence from others suggests that long term administration NPY does produce an increased efficiency of weight gain per calorie consumed. Further work indicates that NPY given into the PVN reduces brown fat expression of the gene for uncoupling protein. We therefore propose study of NPY effects on feeding and metabolism as a new model system for understanding CNS regulation of energy balance. Advantages of the NPY model are reliability, potency, testing in normal animals, testing under a variety of nutritional and environmental circumstances, and potential for localization in the central nervous system of effect. As indicators of energy metabolism, we plan measurements of food energy intake, whole body energy expenditure by calorimetry, body weight and composition measurements, facultative thermogenesis in brown fat by GDP binding and thermogenic potential by measures of uncoupling protein and uncoupling protein mRNA levels, and white fat activity by lipoprotein lipase activity. SPECIFIC QUESTIONS:(l)What is the dose response and time course on NPY administration on energy metabolism? We will test the NPY effect on feeding and metabolism at three durations of stimulation and with several types of control groups designed to control for the effects of diet and hunger.(2) What are the loci of action for NPY-induced changes infeeding and metabolism and are there sites at which only some of the effects are seen? NPY is known to have some effects at several hypothalamic sites. The locus of action of NPY on metabolism is unknown. Are the various effects produced at one or more than one site?(3) Are the effects of NPY on feeding and metabolism independent of diet composition? We will determine whether the macronutrient composition of the diet affects the feeding and metabolic response to NPY.(4) Are the feeding and metabolic changes produced by NPY independent of baseline body energy stores ? We will produce obesity by inducing consumption with a high fat diet and produce underweight rats by restricting food intake,then assess the effect on NPY induced feeding and metabolic changes. (5) Will NPY produce the same effects in VMH and LH lesioned animals?