Nutritional status modify the expression of hypothalamic neuropeptides through various signal molecules, including mitogen-activated protein kinases (MAPKs) and cAMP/calcium-responsive element-binding protein (CREB), for the regulation of energy balance. Previously, we demonstrated fasting-induced activation of extracellular signal-regulated kinase 1/2 (ERK) and p38 mitogen-activated protein kinase (p38) in the murine hypothalamus. To study how caloric intake after food deprivation influences intracellular signal transduction, we investigated the phosphorylation of ERK and p38 in the murine hypothalamus of refed mice. In the arcuate nucleus, refeeding significantly attenuated fasting-induced phosphorylation of ERK and CREB. In the paraventricular nucleus, fasting-induced phosphorylation of ERK and p38 was also significantly decreased by refeeding. Thus, refeeding rapidly reduced the fasting-induced phosphorylation of ERK, p38, and CREB, suggesting that the activation of these signal molecules in the hypothalamus is precisely regulated with feeding status.