Procalcitonin (PCT), the precursor of calcitonin (CT), is a 116 amino acid peptide but PCT itself has no known activity. However, although the C cells of the thyroid gland are the dominant source of circulating CT, PCT and its free bioactive amino-terminal fragment (N-PCT) have been localized in adipocytes, neuroendocrine cells as well as in some hypothalamic regions of primary importance in the regulation of feeding and energy balance. These findings together with the co-elaboration of N-PCT and CT, and N-PCT's sequence conservation during evolution, suggest that N-PCT plays a critical, and as yet undefined, physiological function. We demonstrate here that intracerebroventricular (icv) administration of N-PCT significantly decreased food intake and body weight gain for at least 48 h in conscious, freely moving, and unstressed rats fed ad libitum. These effects were accompanied by a transitory increase in body temperature and a decrease in locomotor activity. Moreover, after icv N-PCT administration, Fos protein, a marker of neuronal activation, was found in regions of primary importance in the integration of hormonal signals for energy homeostasis and feeding. In contrast, ip administration of N-PCT did not elicit any anorectic or catabolic effects. Furthermore, PCT was found in key feeding areas such as the arcuate nucleus of free-feeding rats, and its level was significantly reduced following fasting. These results suggest that N-PCT can function as an endogenous ligand for the CT receptor and may act as a catabolic signalling molecule in the central regulation of feeding behaviour and energy homeostasis.