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，美国18%的成年人被定义为肥胖，超过两倍的人被归类为超重。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，儿童肥胖症和II型糖尿病的发病率急剧上升。该建议的中心假设是，成年期的体重管理是由出生后发育“关键时期”建立的下丘脑摄食回路直接决定的。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，则可能发生体重管理的永久性改变，并导致成年期体重表型异常。下丘脑中食欲和能量消耗的最有效调节剂之一是神经肽Y（NPY）。下丘脑神经肽Y系统在出生后发育过程中存在动态变化，暗示该系统是下丘脑摄食回路正常成熟的关键。这项建议会 研究出生后时期，以1）确定ARH预测发展的功能重要性。2)确定NPY是否在出生后早期发育期间体重管理的调节中起作用。3)确定内源性神经肽Y系统的变化是否与出生后长期过度喂养诱导的肥胖表型有关。这项建议的主要目标是使用多学科的方法来确定是否修改的内源性神经肽Y系统在出生后的发展导致异常的体重管理在成年期。为了确定内源性神经肽Y系统在产后期间调节食物摄入和能量消耗中的作用，我们将使用体内（整个动物的食物摄入和肥胖的变化）和体外（下丘脑外植体中的肽释放和电生理学）生理学和药理学实验的组合，再加上神经解剖学措施（免疫细胞化学和原位杂交）。这些模型中下丘脑NPY系统的变化将与能量消耗和体重状态的外周标志物的变化相关，使用RIA和实时PCR。这些研究将为产后期间操纵NPY进食回路对儿童时期代谢率和体重的影响提供重要见解。了解正常和不正常的发展， 神经回路对于确定成年人肥胖的生理机制和确定可能干预的关键时期至关重要。

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.