Functional analysis and search for novel bioactive peptides associated with regulation of feeding behavior and energy balance.

本研究在大鼠脑提取物中发现了一种新的神经介质U型2受体（NMU2R）激动剂活性。与大鼠NMU相比，该活性通过凝胶过滤以更大的分子质量洗脱。通过纯化和结构鉴定，鉴定出一种新的36残基肽，并将其命名为neuromedin S(NMS)，因为它在下丘脑视交叉上核（SCN）中特异性表达。NMS的c端修饰的七残基序列与NMU相同。药理鉴定表明，NMS和NMU对NMU1R和NMU2R的效价和疗效非常相似。在大鼠脑中，NMS mRNA特异性表达于主昼夜节律起搏器所在的SCN中。在光照/暗循环条件下，SCN中NMS的表达呈现日高峰，而在持续黑暗条件下则保持稳定。脑室内给药NMS可引起大鼠的非光性相移。另一方面，下丘脑室旁核也发现了NMS mRNA的低水平表达，这与摄食的调节密切相关。icv给药NMS诱导的摄食抑制作用强于NMU。这些发现表明，NMS参与了昼夜节律和摄食行为的调节(1)。NMU是哺乳动物中一种有效的内源性厌食和分解代谢信号分子，在我们最近观察到神经medin U敲除（NMU KO）小鼠的不活动和运动减慢之后，我们比较了NMU KO和野生型小鼠的伤害反射和环境适应。结果表明，内源性NMU可能参与了对环境刺激的反射和适应(2)。我们还利用日本鹌鹑阐明了NMU在鸟类物种中的核心作用。内源性NMU在鸟类和哺乳动物的摄食和体温调节中起着重要作用(3)。胃饥饿素是我们实验室从胃中纯化的一种新型肽，胆囊收缩素（CCK）是通过迷走传入神经调节进食的胃肠激素。通过对大鼠CCK A型受体的干扰和电生理研究，探讨了ghrelin与CCK在短期摄食调节中的功能关系。结果表明，迷走神经在决定外周能量平衡中起着至关重要的作用。ghrelin和CCK信号转导的效率可能取决于它们各自血浆浓度的平衡和/或GHS-R和CCK- ar之间的相互作用(4)。少

In this study, we found a novel agonist activity for neuromedin U type 2 receptor(NMU2R) in rat brain extract. This activity was eluted in fractions with a larger molecular mass by gel filtration compared to rat NMU. As a result of purification and structural determination, a novel 36-residue peptide was identified and designated as neuromedin S(NMS), because it is specifically expressed in the suprachiasmatic nuclei(SCN) of the hypothalamus. The C-terminal amidated seven-residue sequence of NMS is identical to that of NMU. Pharmacological characterization indicated that NMS and NMU share quite similar potency and efficacy for both NMU1R and NMU2R. In rat brain, NMS mRNA was specifically expressed in the SCN, which is the site of the master circadian pacemaker. NMS expression in the SCN showed a diurnal peak under light/dark cycling, but remained stable under constant darkness. Intracerebroventricular(ICV) administration of NMS in rats induced nonphotic type phase shifts in the circadi … More an rhythm of locomotor activity. On the other hand, low level expression of NMS mRNA was also found in the paraventricular nuclei of the hypothalamus, which is closely implicated in the regulation of the feeding. ICV-administered NMS induced more potent suppression of feeding than NMU. These findings suggest that NMS is implicated in the regulation of circadian rhythm and feeding behaviour(1).NMU is a potent endogenous anorectic and catabolic signaling molecule in manmalian, Following our recent observations of inactivity and slowed movement in neuromedin U knockout(NMU KO) mice, we compared nociceptive reflexes and environmental adaptation in NMU KO and wild-type mice. The results suggest that endogenous NMU may be involved in reflexes and adaptation to environmental stimuli (2). We also elucidated the central role of NMU in avian species using Japanese quail. Endogenous NMU plays an important role in the regulation of food intake and body temperature in avian species as well as mammalian (3).Ghrelin, a novel peptide purified from stomach in our laboratory, and cholecystokinin(CCK) are gastrointestinal hormones regulating feeding via the vagal afferent nerve. We examined the functional relationship between ghrelin and CCK in the short-term regulation of food intake using rats disrupted CCK type A receptor and electrophysiological study. The results indicate that the vagus nerve plays a crucial role in determining peripheral energy balance. The efficiency of ghrelin and CCK signal transduction may depend on the balance of their respective plasma concentration and/or on interactions between GHS-R and CCK-AR (4). Less