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

arg - le- tyr作为一种血管紧张素l转换酶抑制剂，从油菜籽蛋白的枯草菌素消化液中分离得到，经口服可抑制小鼠的食物摄入。CCK_1受体拮抗剂洛格鲁胺阻断了厌食活性。然而，arg - le- tyr对CCK_1受体没有亲和力，提示其刺激了胆囊收缩素的释放。生长素是一种生长激素促分泌剂。它在氨基末端的第三个位置有辛烷基丝氨酸残基，这是促分泌活性所必需的。Inui等人发现ghrelin具有厌氧活性，而去酰基ghrelin具有厌食活性。我们在胃饥饿素的氨基端合成了辛烷基丝氨酸残基被色氨酸残基取代的五肽类似物。其中[Trp^3， Arg^5]-ghrelin（1-5）对ghrelin受体GHS-R具有亲和力（IC_50=10mM）。口服后刺激生长激素释放，脑室内给药后刺激食物摄入。我们证明了神经紧张素的厌食活性是由组胺释放和H_1受体介导的。我们还发现，口服神经紧张素刺激胆汁酸分泌，降低血清胆固醇水平。我们发现肠抑素，一种内源性厌食肽，在口服后刺激胆汁酸分泌并降低血清胆固醇水平。此外，它还能抑制吗啡的镇痛活性。我们发现补体C5a的促氧活性是由前列腺素（PG） d2和dp受体介导的。我们还发现补体C3a具有厌食活性，这是由PGE_2和ep_4受体介导的。从而阐明了一些内源性肽调节食物摄入的作用方式，并发现了它们新的生物活性。

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.