Analysis of feeding and lipid metabolism regulation by bombesin-like peptide receptors.

为了阐明BRS-3调节摄食和代谢的机制，我们研究了BRS-3与其他摄食调节肽及其受体的关系。在BRS-3基因缺陷的小鼠中，我们发现了吞噬功能亢进、随后的高瘦素血症和脑瘦素抵抗。在促食欲素神经肽中，BRS-3缺陷小鼠对黑色素浓缩激素(MCH)的过度吞噬反应显著增强。此外，下丘脑中MCH-R和MCH mRNAs水平显著升高。根据这些结果，我们推测BRS-3调节瘦素减少MCH/MCH-R信号转导的机制。为了获得条件表达BRS-3的小鼠株系，我们构建了BRS-3的表达载体，并将其导入ES细胞，获得了嵌合小鼠。我们还成功地从鸡脑中克隆了两个蛙皮素样多肽受体chGRP-R和chBRS-3.5。ChGRP-R与哺乳动物和两栖动物的GRP-R高度一致，并且该受体对GRP和蛙皮素都表现出高度的亲和力。ChBRS-3.5与哺乳动物BRS-3和两栖动物Bb4序列相似，对蛙黄素具有中等亲和力，但对GRP和NMB亲和力较低。在雏鸡脑中，chGRP-R主要在下丘脑表达，而chBRS-3.5广泛分布于大脑皮层。这些结果概括了蛙皮素肽受体在脊椎动物中的重要作用。

To clarify the mechanism underlying modulation of feeding and metabolism by BRS-3, we investigated the relationship between BRS-3 and other feeding-regulating peptides and their receptors. In BRS-3-deficient mice, we found hyperphagia, subsequent hyperleptinemia and brain leptin resistance. Among orexigenic neuropeptides, the hyperphagic response to melanin-concentrating hormone (MCH) was significantly enhanced in BRS-3-deficient mice. In addition, the levels of MCH-R and MCH mRNAs in the hypothalamus were significantly elevated. From these results, we assume that the BRS-3 regulate the mechanism by which leptin decreases the MCH/MCH-R signaling. To generate mouse line conditionally expressing BRS-3, we constructed the vector and introduced it into ES cells and obtained the chimeric mice. We also have successfully cloned two bombesin-like peptide receptors, chGRP-R and chBRS-3.5 from chick brain. ChGRP-R is highly identical with mammalian and amphibian GRP-R, and this receptor showed high affinity for both GRP and bombesin. ChBRS-3.5, having sequence similarities to both mammalian BRS-3 and amphibian BB4, showed moderate affinity for bombesin, but low affinity for both GRP and NMB. In chick brain, chGRP-R is expressed predominantly in the hypothalamus whereas chBRS-3.5 is distributed widely in the pallium. These results recapitulate important roles of bombesin peptide receptors in vertebrates.