Christophe J
Department of General and Human Biochemistry, Université Libre de Bruxelles, Brussels, Belgium.
Ann N Y Acad Sci. 1998 Dec 11;865:323-35. doi: 10.1111/j.1749-6632.1998.tb11192.x.
Anitobesity drugs must increase the sensitivity of the hypothalamic satiety center towards leptin and antagonize the synthesis and action of NPY. The array of pharmacologic tools available is vast and presently ineffective. Among peptide analogs considered for evaluation [NPY-5 antagonists and CCK-A, bombesin, amylin and melanocyte-stimulating hormone-4 (or melanin-concentrating hormone?) agonists], is there a place for GLP-1 and PACAP? GLP-1 receptors present in ARC, PVN, VMN, and SON are the target for both central and blood-borne GLP-1 in those hypothalamic neurons endowed with GLUT-2 and glucokinase. GLP-1, hypersecreted by L-cells after a meal, is a potent insulinotropic agent and, together with glucose, reduces food intake and induces c-fos in the ARC. PACAP is present in the ARC, PVN, and SCH, and its hypothalamic type I receptor elevates cAMP and inositol triphosphate in the PVN, where it may perhaps antagonize NPY-induced food intake and hyperinsulinemia. However, irrelevant neuroendocrine, autonomic, and circadian functions are also activated by this peptide, making it a less than ideal base on which to build an obesity treatment.
抗肥胖药物必须提高下丘脑饱腹感中枢对瘦素的敏感性，并拮抗神经肽Y（NPY）的合成及作用。现有的一系列药理手段虽多，但目前都无效。在考虑用于评估的肽类似物中[NPY-5拮抗剂以及胆囊收缩素-A（CCK-A）、蛙皮素、胰淀素和促黑素细胞激素-4（或促黑素浓集激素？）激动剂]，胰高血糖素样肽-1（GLP-1）和垂体腺苷酸环化酶激活肽（PACAP）有一席之地吗？存在于弓状核（ARC）、室旁核（PVN）、腹内侧核（VMN）和视上核（SON）的GLP-1受体，是那些具有葡萄糖转运蛋白2（GLUT-2）和葡萄糖激酶的下丘脑神经元中中枢和血源性GLP-1的作用靶点。进食后由L细胞大量分泌的GLP-1是一种强效促胰岛素分泌剂，与葡萄糖一起可减少食物摄入量并在弓状核诱导c-fos表达。PACAP存在于弓状核、室旁核和视交叉上核（SCH），其下丘脑I型受体可提高室旁核中的环磷酸腺苷（cAMP）和三磷酸肌醇水平，在该区域它可能拮抗NPY诱导的食物摄入和高胰岛素血症。然而，该肽也会激活无关的神经内分泌、自主神经和昼夜节律功能，这使其作为肥胖治疗的基础并不理想。
