Studies on low molecular weight peptides regulating food intake after oral administration

从菜籽蛋白枯草杆菌蛋白消化液中分离得到的血管紧张素-L转换酶抑制剂精氨酸-酪氨酸能抑制小鼠灌胃给药后的摄食量。该作用可被CCK_1受体拮抗剂洛谷胺阻断。然而，Arg-1le-Tyr不与CCK_1受体亲和，提示它能刺激CCK_1的释放。Ghrelin已被分离为生长激素促分泌剂。它在氨基末端的第三个位置上有辛酰Ser残基，这是促分泌素活性所必需的。Inui等人。发现Ghrelin具有促食欲活性，而去酰基Ghrelin具有厌食活性。我们在Ghrelin的氨基末端合成了五肽类似物，其中辛酰丝氨酸残基被色氨酸残基取代。其中，[Trp^3，Arg^5]-ghrelin(1-5)与Ghrelin受体GHS-R有亲和力(IC50=10 mM)。口服后促进生长激素释放，侧脑室注射后促进摄食。我们证明神经降压素的厌食活性是通过组胺释放和H_1受体介导的。我们还发现神经降压素在口服后刺激胆汁酸的分泌和降低血清胆固醇水平。我们发现肠抑素是一种内源性厌食肽，在口服后刺激胆汁酸的分泌和降低血清胆固醇水平。我们发现补体C5a的促食欲活性是由前列腺素(PG)D2和DP受体介导的。我们还发现补体C3a具有由PGE_2和EP_4受体介导的厌食活性，从而阐明了一些调节食物摄入的内源性多肽的作用方式，并发现了它们的新的生物活性。

Arg-lle-Tyr, which has been isolated as an inhibitor for angiotensin l-converting enzyme from subtilisin digest of rape seed protein suppressed food intake after oral administration in mice. The anorectic activity was blocked by lorglumide, an antagonist for CCK_1 receptor. However, Arg-lle-Tyr did not have affinity for CCK_1 receptor, suggesting that it stimulated release of cholecystokinin.Ghrelin has been isolated as a growth hormone secretagogue. It has octanoyl Ser residues at the third position from the amino terminus, which is essential for the secretagogue activity. Inui et al. found that ghrelin has an orexigenic activity while desacyl ghrelin has an anorectic activity. We synthesized pentopeptide anologues at the amino terminus of ghrelin, in which octanoyl Ser residue is replaced with Trp residue. Among them, [Trp^3, Arg^5]-ghrelin (1-5) showed affinity for ghrelin receptor GHS-R (IC_50=10mM). It stimulated growth hormone release after oral administration, and food intake after intracerebroventriculdr administration.We demonstrated that an anorectic activity of neurotensin is mediated by histamine release and H_1 receptor. We also found that neurotensin stimulated bile acid secretion and reduced serum cholesterol level after oral administration.We found that enterostatin, an endogenous anorectic peptide, stimulated bile acid secretion and reduced serum cholesterol level after oral administration. Furthermore, it suppressed analgesic activity of morphin.We found that an orexigenic activity of complement C5a is mediated by prostaglandin (PG) D_2 and DP-receptor. We also found that complement C3a has an anorectic activity which is mediated by PGE_2 and EP_4-receptor.Thus, mode of action of some endogenous peptides regulating food intake have been clarified, and their new biological activities have been found.