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?
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