NPY Feeding Circuits during Development

开发期间的 NPY 馈送电路

• 批准号: 6744741
• 负责人: KEVIN L GROVE
• 金额: $ 22.56万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744741
• 关键词: appetite; appetite regulatory center; bioenergetics; body weight; developmental neurobiology; dietary excess; electrophysiology; glutamates; hypothalamus; immunocytochemistry; in situ hybridization; laboratory rat; melanocyte stimulating hormone; neural plasticity; neuropeptide Y; nutrient intake activity; nutrition related tag; obesity; phenotype; polymerase chain reaction; radioimmunoassay; weight control

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.

现在，肥胖被认为是全球健康问题，这是导致冠心病和II型糖尿病发病率增加的主要贡献者。到1998年，美国有18％的成年人被定义为肥胖，大于该数字超重的两倍。此外，美国肥胖成年人的数量每年以0.7％的速度增加。更令人不安的是儿童肥胖和II型糖尿病的急剧增加。该提议的中心假设是，成年期间的体重管理直接取决于在出生后“关键时期”期间建立的下丘脑喂养电路。此外，如果在神经可塑性的“关键时期”中发生能量平衡中的扰动，则可能会发生体重管理的永久改变，并导致成年期间体重异常。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NPY系统在产后发育过程中存在动态变化，这意味着该系统是下丘脑进食电路适当成熟的关键。该提议将 研究产后时期至1）确定ARH预测发展的功能重要性。 2）确定NPY在产后早期发育期间的体重管理调节中是否起作用。 3）确定内源性NPY系统中的变化是否负责产后慢性过度喂养引起的肥胖表型。该提案的主要目的是使用多学科方法来确定产后发育过程中内源性NPY系统的修改是否会导致成年期间异常体重管理。为了确定内源性NPY系统在产后期间的食物摄入和能量消耗调节中的作用，我们将使用体内（全动物的食物摄入量和脂肪的变化）和体外（肽释放和电生理学的变化）（在有假识探险剂中的肽释放和电生理学）与Neurolational和药物学实验性的（无丘脑的实验）（counamic offore）（肽）的生理学和药物学实验（无效）原位杂交）。这些模型中下丘脑NPY系统的变化将与使用RIA和实时PCR的能量消耗和体重状态的外围标记变化有关。这些研究将在产后对童年时期的代谢率和体重进行操纵的后果提供重要的见解。理解这一点的正常和异常发展 电路对于确定成年肥胖和确定可能干预的关键时期的生理机制至关重要。