The melanocyte-stimulating hormone (-MSH), derived from proopiomelanocortin (POMC), is generated by a post-translational processing mechanism involving the prohormone convertase (PCs), PC1/3 and PC2. In the brain, -MSH is produced in the arcuate nucleus (ARC) of the hypothalamus and in the nucleus of the solitary tract (NTS) of the medulla. This peptide is key in controlling energy balance as judged by changes observed at transcriptional level. However, little information is available regarding the biosynthesis of the precursor POMC and the production of its processed peptides during feeding, fasting, and fasting plus leptin in the ARC as compared to the NTS in conjunction with the PCs activity. In this study, we found that in the ARC, pomc mRNA, POMC-derived peptides and PC1/3 all decreased during fasting, and administration of leptin reversed these effects. In contrast in the NTS, where there is a large amount of a 28.1-kDa peptide similar in size to POMC, the 28.1-kDa peptide and other POMC-derived peptides including -MSH were further accumulated in fasting conditions, whereas pomc mRNA decreased. These changes were not reversed by leptin. We also observed that during fasting, PC2 levels decreased in the NTS. These data suggest that in the NTS, fasting induced changes in POMC biosynthesis and processing is independent of leptin. These observations indicate that changes in energy status affect POMC in the brain in a tissue-specific manner. This represents a novel aspect in the regulation of energy balance and may have implications in the pathophysiology of obesity.