Implications of mastication in energy intake and expenditure regulated by histamine (HA) neurons were investigated in rats. Depletion of neuronal HA from the mesencephalic trigeminal sensory nucleus (Me5) reduced eating speed, but that from a satiety center of the ventromedial hypothalamus (VMH) increased both meal size and its duration leaving eating speed unaffected. Turnover of neuronal HA in the Me5 was elevated at the early phase of feeding and that in the VMH was at the later phase. This elevated turnover was abolished by gastric intubations of an isocaloric liquid diet or an equivolume of water. Mastication-induced activation of HA neurons suppressed physiological food intake through H1-receptor in the hypothalamic paraventricular nucleus (PVN) and the VMH. On the other hand, the HA neurons activation accelerated lipolysis particularly in the visceral adipose tissues and up-regulated mRNA expression of uncoupling protein family through sympathetic efferent nerve. Mastication thus plays an important role as a potent input signal to activate HA neurons. Our recent findings have evidently shown how tightly and elegantly HA neurons are concordant with leptin signaling system through a negative feedback loop.