NEUROPEPTIDE Y--EFFECTS ON ENERGY METABOLISM

这项建议的重点是中央控制器的可能性 能量新陈代谢可能存在，一个控制器不仅影响 食物摄入，但提供能量代谢的补充调节，如 井。例如，这样的中央机制将产生积极的影响 能量平衡(和肥胖)通过同时增加食物摄入量， 减少产热，增加白色脂肪中的能量储存。我们 研究了黄油对棕色和白色脂肪活性的影响。 脑室注射NPY，增加食物摄入量， 显着降低棕色脂肪的生热活性，并大大 白色脂肪中脂蛋白脂肪酶活性增加(提示 增加卡路里储存)。进一步的工作表明，这些 NPY的新陈代谢效应与食物摄入量无关 同样的方式，当食物摄取是为了控制动物，或者甚至当没有 允许进食。其他人的证据表明，从长远来看 服用NPY确实可以提高体重增加的效率 每消耗一卡路里。进一步的研究表明，NPY被注入PVN 减少棕色脂肪解偶联蛋白基因的表达。我们 因此，提出研究NPY对摄食和代谢的影响作为一种新的 理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、效度、正常测试 动物，在各种营养和环境下进行测试 中枢神经定位的环境和潜力 效力制度。作为能量新陈代谢的指标，我们计划 食物能量摄入量、全身能量消耗的测量 兼职的量热法、体重和成分测量 棕色脂肪中GDP结合的生热作用和 解偶联蛋白和解偶联蛋白信使核糖核酸水平的测定 白色脂肪的活性由脂蛋白脂酶活性决定。 具体问题：(L)剂量反应和时间进程是什么 NPY对能量代谢的影响？我们将测试NPY效应在 在三个持续时间的刺激下的摄食和代谢 旨在控制饮食和饮食影响的控制组的类型 饥饿。(2)NPY诱导的进食变化的作用轨迹是什么 和新陈代谢，有没有只有部分影响的部位 看到了吗？已知NPY在下丘脑的几个部位有一些影响。 NPY在新陈代谢中的作用机制尚不清楚。是不同的 在一个或多个地点产生的影响？(3)NPY的影响 与饮食构成无关的摄食和新陈代谢？我们会 确定饮食中的常量营养素成分是否会影响 对NPY的摄食和代谢反应。(4)是摄食和代谢 NPY产生的变化与基线身体能量储存无关？我们 会通过高脂肪饮食诱导消费而导致肥胖 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会生产吗？ 在VMH和LH损毁的动物中有相同的效果吗？

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?