Mounien Lourdes, Do Rego Jean-Claude, Bizet Patrice, Boutelet Isabelle, Gourcerol Guillaume, Fournier Alain, Brabet Philippe, Costentin Jean, Vaudry Hubert, Jégou Sylvie
INSERM U 413, Laboratory of Cellular and Molecular Neuroendocrinology, University of Rouen, Mont-Saint-Aignan, France.
Neuropsychopharmacology. 2009 Jan;34(2):424-35. doi: 10.1038/npp.2008.73. Epub 2008 Jun 4.
Pituitary adenylate cyclase-activating polypeptide (PACAP) and the proopiomelanocortin (POMC)-derived peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), exert anorexigenic activities. While alpha-MSH is known to inhibit food intake and stimulate catabolism via activation of the central melanocortin-receptor MC4-R, little is known regarding the mechanism by which PACAP inhibits food consumption. We have recently found that, in the arcuate nucleus of the hypothalamus, a high proportion of POMC neurons express PACAP receptors. This observation led us to investigate whether PACAP may inhibit food intake through a POMC-dependent mechanism. In mice deprived of food for 18 h, intracerebroventricular administration of PACAP significantly reduced food intake after 30 min, and this effect was reversed by the PACAP antagonist PACAP6-38. In contrast, vasoactive intestinal polypeptide did not affect feeding behavior. Pretreatment with the MC3-R/MC4-R antagonist SHU9119 significantly reduced the effect of PACAP on food consumption. Central administration of PACAP induced c-Fos mRNA expression and increased the proportion of POMC neuron-expressing c-Fos mRNA in the arcuate nucleus. Furthermore, PACAP provoked an increase in POMC and MC4-R mRNA expression in the hypothalamus, while MC3-R mRNA level was not affected. POMC mRNA level in the arcuate nucleus of PACAP-specific receptor (PAC1-R) knock-out mice was reduced as compared with wild-type animals. Finally, i.c.v. injection of PACAP provoked a significant increase in plasma glucose level. Altogether, these results indicate that PACAP, acting through PAC1-R, may inhibit food intake via a melanocortin-dependent pathway. These data also suggest a central action of PACAP in the control of glucose metabolism.
垂体腺苷酸环化酶激活多肽（PACAP）和源自阿黑皮素原（POMC）的肽α-促黑素细胞激素（α-MSH）具有抑制食欲的活性。虽然已知α-MSH通过激活中枢黑皮质素受体MC4-R来抑制食物摄入并刺激分解代谢，但关于PACAP抑制食物消耗的机制知之甚少。我们最近发现，在下丘脑弓状核中，很大一部分POMC神经元表达PACAP受体。这一观察结果促使我们研究PACAP是否可能通过依赖POMC的机制抑制食物摄入。在禁食18小时的小鼠中，脑室内注射PACAP在30分钟后显著减少食物摄入量，并且这种作用被PACAP拮抗剂PACAP6-38逆转。相比之下，血管活性肠肽不影响进食行为。用MC3-R/MC4-R拮抗剂SHU9119预处理可显著降低PACAP对食物消耗的影响。中枢给予PACAP可诱导c-Fos mRNA表达，并增加弓状核中表达c-Fos mRNA的POMC神经元比例。此外，PACAP可促使下丘脑POMC和MC4-R mRNA表达增加，而MC3-R mRNA水平不受影响。与野生型动物相比，PACAP特异性受体（PAC1-R）敲除小鼠弓状核中的POMC mRNA水平降低。最后，脑室内注射PACAP可使血浆葡萄糖水平显著升高。总之，这些结果表明，PACAP通过PAC1-R起作用，可能通过依赖黑皮质素的途径抑制食物摄入。这些数据还提示PACAP在控制葡萄糖代谢中具有中枢作用。
