Melanocortin-3 receptors (Mc3rs) in the central nervous system are involved in expression of anticipatory rhythms and synchronizing clocks maintaining circadian rhythms during restricted feeding (RF) [mice housed under a 12-h light-dark cycle with lights on between zeitgeber time (ZT) 0 to ZT12 fed 60% of normal calories between ZT7 and ZT11]. Because the systems governing circadian rhythms are important for adaptation to RF, we investigated whether Mc3rs are required for metabolic adaption to RF. Mc3r(-/-) mice subjected to RF exhibited normal weight loss; however, they developed hyperinsulinemia, glucose intolerance, increased expression of lipogenic genes, and increased ketogenesis relative to controls. Rhythmic expression of transcription factors regulating liver clock activity and energy metabolism (Bmal1, Rev-erbalpha, Pgc1, Foxo1, Hnf4alpha, and Pck1) was severely compromised in Mc3r(-/-) mice during RF. Inhibition of neural melanocortin receptors by agouti-related peptide also attenuated rhythmicity in the hepatic expression of these genes during RF. Collectively, these data suggest that neural Mc3rs are important for adapting metabolism and maintaining rhythms of liver metabolism during periods when feeding is restricted to the light cycle.-Sutton, G. M., Begriche, K., Kumar, K. G., Gimble, J. M., Perez-Tilve, D., Nogueiras, R., McMillan, R. P., Hulver, M. W., Tschöp, M. H., Butler, A. A. Central nervous system melanocortin-3 receptors are required for synchronizing metabolism during entrainment to restricted feeding during the light cycle.