The injection of a melanocortin peptide or of melanocortin peptide analogues into the cerebrospinal fluid or into the ventromedial hypothalamus in nanomolar or subnanomolar doses induces a long-lasting inhibition of food intake. The effect keeps significant for up to 9 h and has been observed in all animal species so far tested, the most susceptible being the rabbit. The anorectic effect of these peptides is a primary one, not secondary to the shift towards other components of the complex melanocortin-induced behavioral syndrome, in particular grooming. The site of action is in the brain, and the effect is not adrenal-mediated because it is fully exhibited also by adrenalectomized animals. It is a very strong effect, because the degree of feeding inhibition is not reduced in conditions of hunger, either induced by 24 h starvation, or by insulin-induced hypoglycemia, or by stimulation of gamma-aminobutyric acid (GABA), noradrenergic or opioid systems. The microstructural analysis of feeding behavior suggests that melanocortins act as satiety-inducing agents, because they do not significantly modify the latencies to start eating, but shorten the latencies to stop eating. The mechanism of action involves the activation of melanocortin MC(4) receptors, because selective melanocortin MC(4) receptor antagonists inhibit the anorectic effect of melanocortins, while inducing per se a strong stimulation of food intake and a significant increase in body weight. Melanocortins seem to play an important role in stress-induced anorexia, because such condition, in rats, is significantly attenuated by the blockage of melanocortin MC(4) receptors; such a role is not secondary to an increased release of corticotropin-releasing factor (CRF), because, on the other hand, the CRF-induced anorexia is not affected at all by the blockage of melanocortin MC(4) receptors. The physiological meaning of the feeding inhibitory effect of melanocortins, and, by consequence, the physiological role of melanocortins in the complex machinery responsible for body weight homeostasis, is testified by the hyperphagia/obesity syndromes caused by mutations in the pro-opiomelanocortin (POMC) gene, or in the melanocortin MC(4) receptor gene, or in the agouti locus. Finally, recent evidences suggest that melanocortins could be involved in mediating the effects of leptin, and in controlling the expression of neuropeptide Y (NPY).

译文

:以纳摩尔或亚纳摩尔剂量向脑脊液或腹膜下丘脑中注射黑皮质素肽或黑皮质素肽类似物可长期抑制食物摄入。效果可保持长达9小时,并且在迄今为止测试的所有动物物种中均已观察到,最易感的是兔子。这些肽的厌食作用是主要的,而不是向复杂的黑皮质素诱导的行为综合症,特别是修饰的其他成分转变的次要作用。作用部位在大脑中,并且该作用不受肾上腺介导,因为肾上腺切除术动物也充分发挥了作用。这是非常有效的作用,因为在饥饿状态下(饥饿24小时,胰岛素诱导的低血糖症或通过γ-氨基丁酸(GABA),去甲肾上腺素能或阿片类物质刺激而导致的饥饿感),进食抑制的程度不会降低系统。进食行为的微观结构分析表明,黑皮质素可作为饱腹感的诱因,因为它们不会显着改变开始进食的潜伏期,但会缩短停止进食的潜伏期。该作用机制涉及黑皮质素MC(4)受体的激活,因为选择性的黑皮质素MC(4)受体拮抗剂抑制黑皮质素的厌食作用,同时本身引起强烈的食物摄取刺激和体重的显着增加。黑皮质素似乎在应激性厌食症中起重要作用,因为在大鼠中,这种状况因黑皮质素MC(4)受体的阻滞而明显减弱。这种作用并不是促肾上腺皮质激素释放因子(CRF)释放增加的继发因素,因为另一方面,CRF引起的厌食症完全不受黑皮质素MC(4)受体的阻滞影响。黑色素皮质激素的进食抑制作用的生理意义,以及由此导致的黑色素皮质激素在引起体重动态平衡的复杂机制中的生理作用,已由前opiomelanocortin(POMC)突变引起的食欲亢进/肥胖症综合症得到证实。黑素皮质素MC(4)受体基因中的基因,或者在刺豚鼠基因座中。最后,最近的证据表明,黑皮质素可能参与调节瘦素的作用,并参与控制神经肽Y(NPY)的表达。

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