Hypothalamic Prolyl carboxypeptidase (PRCP) plays a role in the regulation of energy metabolism by inactivating hypothalamic α-melanocyte stimulating hormone (α-MSH) levels and thus affecting melanocortin signaling. Alpha-MSH production is highly regulated both at transcriptional and posttranslational levels. Here we show that fasting induces a hypothalamic-specific up-regulation of Prcp mRNA and protein levels. Since fasting is characterized by elevated circulating ghrelin levels, we tested the effect of peripheral and central administration of ghrelin, and found that ghrelin increases hypothalamic Prcp mRNA expression. No changes in Prcp mRNA levels were detected in ghrelin knockout mice compared to their controls. Finally, ghrelin effect on PRCP expression was ghrelin receptor-mediated. Altogether our data show that ghrelin is a key regulator of hypothalamic PRCP expression, and up-regulation of PRCP by ghrelin may be an additional mechanism to decrease melanocortin signaling.