The hypothalamic circuits controlling food intake and body weight receive and integrate information from circulating satiety signals such as leptin and insulin and also from ghrelin, the only known circulating hormone that stimulates appetite following systemic injection. Activation of arcuate neurons by ghrelin and ghrelin mimetics (the growth hormone secretagogues) is augmented in 48-h-fasted rats compared with fed rats, as reflected by a greater number of cells expressing Fos protein in response to administration of the same maximally effective dose. Here we sought to determine whether this increased responsiveness in fasting might reflect or be influenced by low levels of circulating satiety factors such as leptin or insulin. Chronic central infusion of insulin or leptin during a 48-h fast suppressed the threefold increase in the Fos response to intravenous injection of a maximally effective dose of growth hormone-releasing peptide (GHRP)-6, a synthetic growth hormone secretagogue. This appears to be a direct central action of insulin and leptin because the marked decrease in plasma levels of insulin, leptin, and glucose during fasting were unaffected by central administration of either hormone. Furthermore, the GHRP-6-induced Fos response was twofold greater in obese leptin- and insulin-resistant Zucker rats compared with lean controls. These data provide evidence that the ghrelin-sensitive circuits in the hypothalamus are dynamically regulated by central insulin and leptin action.