Molecular Mechanisms of NPY-induced Feeding in Rats

描述(申请人提供)：神经肽Y(NPY)是哺乳动物大脑中存在的一种高浓度存在的36个氨基酸的多肽。将NPY注射到下丘脑区可引起大鼠强烈的摄食反应，NPY与糖尿病和肥胖症密切相关。外周饱腹感因子瘦素已被证明通过抑制下丘脑部位NPY的合成和释放而对小鼠和大鼠产生饱腹感刺激，而下丘脑部位是已知的调节进食行为的部位。最重要的是，PYY3-36，一种餐后从肠道L细胞释放到循环中的神经肽Y的外周同系物，据报道起到了饱腹感的信号。在人类中服用PYY 3-36显著降低食欲，并在长达24小时的时间内使食物摄入量减少33%。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%，预计糖尿病人数将大幅增加。超重和肥胖还会增加患高胆固醇血症和心脏病等其他问题的风险。为了了解饮食失调和肥胖的原因，我们建议阐明调控NPY诱导下丘脑摄食的分子机制。 NPY激活下丘脑室旁核中NPY的Y1和Y5受体，通过抑制cAMP的积聚和细胞内钙的动员来触发饥饿信号。这两个重要的第二信使激活了转录因子CREB，该转录因子的激活调节了许多依赖于CREB的基因。这些生化事件转化为饥饿的信号。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信号转导级联和参与维持能量动态平衡的调控基因。在目前的研究方案中，我们将研究三个具体目标：L)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的活性，2)研究食物诱导的肠肽PYY3-36的释放是否抑制CREB的活性以引发饱感信号，以及3)确定Y1和Y5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症发生的分子基础和制定治疗计划至关重要。

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.