To explore the effect of refeeding on recovery of thyrotropin-releasing hormone (TRH) gene expression in the hypothalamic paraventricular nucleus (PVN) and its correlation with the feeding-related neuropeptides in the arcuate nucleus (ARC), cFos immunoreactivity in the PVN and ARC 2h after refeeding and hypothalamic TRH, NPY and AGRP mRNA levels 4, 12, and 24 h after refeeding were studied in Sprague-Dawley rats subjected to prolonged fasting. Despite rapid reactivation of POMC neurons by refeeding as demonstrated by cFos-immunoreactivity (IR) in ARC -MSH-IR neurons and ventral parvocellular subdivision PVN neurons, cFos-IR was present in only 9.7±1.1% of hypophysiotropic TRH neurons. Serum TSH levels remained suppressed 4 and 12h after the start of refeeding, returning to fed levels after 24h. Fasting reduced TRH mRNA compared to fed animals, and similar to TSH, remained suppressed at 4 and 12h following refeeding, returning toward normal at 24h. AGRP and NPY gene expression in the ARC were markedly elevated in fasting rats, AGRP mRNA returning to baseline levels 12h after refeeding and NPY mRNA remaining persistently elevated even at 24h. These data raise the possibility that refeeding-induced activation of melanocortin signaling exerts differential actions on its target neurons in the PVN, an early action directed at neurons that may be involved in satiety, and a later action on hypophysiotropic TRH neurons involved in energy expenditure, potentially mediated by sustained elevations in AGRP and NPY. This response may be an important homeostatic mechanism to allow replenishment of depleted energy stores associated with fasting.