Molecular Mechanisms of NPY-induced Feeding in Rats

NPY诱导大鼠喂养的分子机制

• 批准号: 6896229
• 负责人: SULAIMAN T SHERIFF
• 金额: $ 22.84万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896229
• 关键词: appetite regulatory center; biological signal transduction; cAMP response element binding protein; cyclic AMP; enzyme linked immunosorbent assay; gene expression; hypothalamic hormones; hypothalamus; laboratory rat; leptin; neurohormones; neuropeptide Y; nutrient intake activity; obesity; polymerase chain reaction; regulatory gene; satiations; second messengers

DESCRIPTION (provided by applicant): Neuropeptide Y (NPY) is a 36 amino acid peptide present in high concentration in mammalian brain. Injection of NPY into hypothalamic regions elicits a powerful feeding response in rats, and NPY has been strongly implicated in diabetes and obesity. The peripheral satiety factor, leptin, has been shown to exert a satiety stimuli in mice and rats by inhibiting the synthesis and release of NPY in hypothalamic sites that are known to regulate eating behavior. Most importantly, PYY 3-36, a peripheral homologue of NPY released from the L-cells of the gut into the circulation after a meal, is reported to act as a satiety signal. Administration of PYY 3-36 in humans significantly decreased appetite and attenuated food intake by 33 percent for up to 24 hours. Recent surveys show that obesity in USA has increased from 17.9 percent in 1998 to 18.9 percent in 1999, and a sharp increase in diabetes is expected. Excess body weight and obesity also increase the risk of other problems such as hypercholesterolemia and heart disease. In an attempt to understand the causes of eating disorders and obesity, we propose to elucidate the molecular mechanisms regulating NPY-induced feeding in the hypothalamus. Activation of Y1 and Y5 receptors of NPY in the hypothalamic PVN by NPY trigger the hunger signal by inhibiting cAMP accumulation and mobilizing intracellular Ca++. These two prominent second messengers activate a transcription factor, CREB, the activation of which regulates many CREB-dependent genes. These biochemical events translate into a hunger signal. PYY 3-36 activates hypothalamic Y2 receptors to turn off the hunger stimuli. Our long-term goal is to investigate the signal transduction cascade and the regulatory genes involved in maintaining energy homeostasis. In ,the present research proposal we will investigate three specific aims:l) To determine whether the changes in the circulating hormones that regulate feeding behavior alter hypothlamic cAMP/PKA and phosphoCREB activities, 2) To investigate whether the food-induced release of gut peptide PYY 3-36 blunts the activity of CREB to elicit a satiety signal, and 3) To determine whether Y1 and Y5 receptor subtypes act through the inhibition of cAMP and stimulation of CREB signaling system. These findings are critical to understanding the molecular bases of obesity development and to develop a treatment plan.

描述（由申请人提供）：神经肽Y（NPY）是一种36个氨基酸的肽，在哺乳动物脑中以高浓度存在。下丘脑注射神经肽Y可引起大鼠强烈的摄食反应，并且神经肽Y与糖尿病和肥胖密切相关。外周饱腹感因子瘦素（leptin）已被证明通过抑制下丘脑中已知调节进食行为的部位中的NPY的合成和释放而在小鼠和大鼠中施加饱腹感刺激。最重要的是，PYY 3-36，一种在餐后从肠道L细胞释放到循环中的NPY的外周同源物，据报道充当饱腹感信号。PYY 3-36在人体中的施用显著降低食欲，并使食物摄入量减少33%，持续长达24小时。最近的调查显示，美国的肥胖率已从1998年的17.9%上升到1999年的18.9%，预计糖尿病患者将急剧增加。超重和肥胖也会增加其他问题的风险，如高胆固醇血症和心脏病。在试图了解饮食失调和肥胖的原因，我们建议阐明的分子机制，调节NPY诱导的摄食下丘脑。 NPY激活下丘脑室旁核中NPY的Y1和Y 5受体，通过抑制cAMP积累和动员细胞内Ca++触发饥饿信号。这两个突出的第二信使激活转录因子CREB，其激活调节许多CREB依赖性基因。这些生物化学事件转化为饥饿信号。PYY 3-36激活下丘脑Y2受体以关闭饥饿刺激。我们的长期目标是研究参与维持能量稳态的信号转导级联和调控基因。在本研究中，我们将研究三个具体目标：1）确定调节摄食行为的循环激素的变化是否改变下丘脑cAMP/PKA和磷酸化CREB活性，2）研究食物诱导的肠肽PYY 3-36的释放是否减弱CREB活性以引起饱腹感信号，3）确定Y1和Y 5受体亚型是否通过抑制cAMP和刺激CREB信号系统起作用。这些发现对于理解肥胖发展的分子基础和制定治疗计划至关重要。

项目成果

Regulation of acid-base transporters by vasopressin in the kidney collecting duct of Brattleboro rat.

布拉特尔伯勒大鼠肾集合管中加压素对酸碱转运蛋白的调节。

• DOI: 10.1159/000093305
• 发表时间: 2006
• 期刊: American journal of nephrology
• 影响因子: 4.2
• 作者: Amlal,Hassane;Sheriff,Sulaiman;Faroqui,Somia;Ma,Liyun;Barone,Sharone;Petrovic,Snezana;Soleimani,Manoocher
• 通讯作者: Soleimani,Manoocher