NPY Feeding Circuits during Development

肥胖现在被认为是一个全球性的健康问题，是冠心病和II型糖尿病发病率增加的主要原因。到1998年，18%的美国成年人被定义为肥胖，而超重的人数是这个数字的两倍多。此外，美国肥胖成年人的数量正以每年0.7%的速度增长。更令人不安的是儿童肥胖和II型糖尿病的急剧增加。该建议的中心假设是，成年期的体重管理直接取决于在出生后发育的“关键时期”建立的下丘脑喂养回路。此外，如果在神经可塑性的“关键时期”暴露于能量平衡的扰动，可能会发生体重管理的永久性改变，并导致成年期体重表型异常。下丘脑食欲和能量消耗最有效的调节剂之一是神经肽Y （NPY）。下丘脑NPY系统在出生后发育过程中发生动态变化，暗示该系统对下丘脑喂养回路的适当成熟至关重要。这项建议将

Obesity is now considered a worldwide health concern, being a major contributor to the increased incidences of coronary heart disease and type II diabetes. By 1998, 18% of the adults in the United states were defined as being obese, with greater than twice that number categorized as overweight. Furthermore, the number of obese adults in the United States is increasing at a rate of 0.7% per year. Even more disturbing is the dramatic increase in obesity and type II diabetes among children. The central hypothesis of this proposal is that body weight management during adulthood is directly determined by the hypothalamic feeding circuits established during a "critical period" postnatal development. Furthermore, if exposure to perturbations in energy balance occurs during this "critical period" of neural plasticity, permanent alterations in body weight management may occur and lead to abnormal body weight phenotypes during adulthood. One of the most potent modulators of appetite and energy expenditure in the hypothalamus is neuropeptide Y (NPY). There are dynamic changes in the hypothalamic NPY system during postnatal development that implicate this system as being pivotal for the proper maturation of hypothalamic feeding circuitry. This proposal will study the postnatal period to 1) Determine the functional importance of the development of ARH projections. 2) Determine if NPY plays a role in the regulation of body weight management during early postnatal development. 3) Determine if changes in the endogenous NPY system are responsible for the obese phenotype induced by chronic overfeeding during the postnatal period. The main goal of this proposal is to use a multidisciplinary approach to determine if modification of the endogenous NPY system during postnatal development leads to abnormal body weight management during adulthood. To identify the role of the endogenous NPY system in the regulation of food intake and energy expenditure during the postnatal period we will use a combination of in vivo (changes in food intake and adiposity in whole animals) and in vitro (peptide release and electrophysiology in hypothalamic explants) physiological and pharmacological experiments, coupled with neuroanatomical measures (immunocytochemistry and in situ hybridization). The changes in the hypothalamic NPY system in these models will be correlated with changes in peripheral markers of energy expenditure and body weight status, using RIA and real-time PCR. These studies will provide important insight into the consequences of manipulation of the NPY feeding circuits, during the postnatal period on metabolic rate and body weight during childhood. Understanding of the normal and abnormal development of this circuitry is critical to determining the physiological mechanisms that underlie adult obesity and identify a critical period for possible intervention.