The anorexigenic and hypertensive effects of nesfatin-1 are reversed by pretreatment with an oxytocin receptor antagonist.

Nesfatin-1 is an 82-amino acid protein encoded by the nucleobindin2 gene. When injected intracerebroventricularly, nesfatin-1, via a melanocortin 3/4 receptor-dependent mechanism, potently decreased both food and water intakes and elevated mean arterial pressure in a dose-related manner. Because nesfatin-1 colocalized with oxytocin in hypothalamus and because nesfatin-1 had direct depolarizing effects on oxytocin-producing neurons in hypothalamic slice preparations, we hypothesized that the actions of nesfatin-1 required the presence of functional oxytocin receptors. We, therefore, pretreated conscious, unrestrained male rats with the oxytocin receptor antagonist, ornithine vasotocin (OVT), before treatment with nesfatin-1. We found that pretreatment with OVT reversed the effects of nesfatin-1 on both food and water intake and on mean arterial pressure, indicating that the central oxytocin system is a downstream mediator of these actions of nesfatin-1. Additionally, we found that OVT reversed the anorexigenic effect of alpha-melanocyte-stimulating hormone (alpha-MSH), suggesting that the central oxytocin system is downstream of the central melanocortin system. Taken together, these data suggest that nesfatin-1 acts through a serial neuronal circuit, in which nesfatin-1 activates the central melanocortin system, which, in turn, acts through the central oxytocin system, leading to an inhibition of food and water intake and an increase in mean arterial pressure.