Role of melanocortins in the central control of feeding

The injection of a melanocortin peptide or of melanocortin peptide analogue s into the cerebrospinal fluid or into the ventromedial hypothalamus in nan omolar or subnanomolar doses induces a long-lasting inhibition of food inta ke. 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 a norectic effect of these peptides is a primary one, not secondary to the sh ift 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 ad renalectomized animals. It is a very strong effect, because the degree of f eeding 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 micros tructural analysis of feeding behavior suggests that melanocortins act as s atiety-inducing agents, because they do not significantly modify the latenc ies to start eating, but shorten the latencies to stop eating. The mechanis m of action involves the activation of melanocortin MC4 receptors, because selective melanocortin MC4 receptor antagonists inhibit the anorectic effec t of melanocortins, while inducing per se a strong stimulation of food inta ke 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 MC4 receptors ; such a role is not secondary to an increased release of corticotropin-rel easing factor (CRF), because, on the other hand, the CRF-induced anorexia i s not affected at all by the blockage of melanocortin MC4 receptors. The ph ysiological meaning of the feeding inhibitory effect of melanocortins, and, by consequence, the physiological role of melanocortins in the complex mac hinery responsible for body weight homeostasis, is testified by the hyperph agia/obesity syndromes caused by mutations in the pro-opiomelano-cortin (PO MC) gene, or in the melanocortin MC4 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 neuro peptide Y (NPY). (C) 2000 Elsevier Science B.V. All rights reserved.