Melatonin is a neuroendocrine transducer of circadian/circannual rhythms able to synchronize organism's physiological activity. On the basis of our recent findings on appetite regulation by melatonin in the zebrafish brain, the aim of this study was to evaluate melatonin's role in peripheral circuitries regulating food intake, growth, and lipid metabolism. For this purpose, the effect of two melatonin doses (100 nM and 1 μM) administered for 10 days, via water, to adult zebrafish was evaluated at both physiological and molecular levels. The major signals controlling energy homeostasis were analyzed together. Additionally, the effect of melatonin doses on muscle metabolic resources was evaluated. The results obtained indicate that melatonin reduces food intake by stimulating molecules involved in appetite inhibition, such as leptin (LPT), in the liver and intestine and MC4R, a melanocortin system receptor, in the liver. Moreover, melatonin decreases hepatic insulin-like growth factor-I ( IGF-I ) gene expression, involved in growth process and other signals involved in lipid metabolism such as proliferator-activated receptors ( PPAR α, β, and γ) and sterol regulatory element-binding protein ( SREBP ). These results were correlated with lower levels of lipids in the muscles as evidenced by the macromolecular pools analyses. The findings obtained in this study could be of great interest for a better understanding of the molecular mechanisms as the basis of food intake control and, in turn, can be a useful tool for medical and aquaculture applications.