Energy balance is monitored by the hypothalamus, which responds to peripheral signals by releasing neuropeptides that regulate energy intake and expenditure. In this study, we constructed pro-opiomelanocortin (POMC) and "cocaine and amphetamine-related transcript" (CART) promoter-driven luciferase plasmids and transformed them permanently into both N29-2 neuronal cells and human SHSY5Y cells. Using reporter gene assays, we identified apigenin from the seeds of Perilla frutescens Britton var crispa (Benth.) using activity-guided fractionation. The 50% promoting concentrations (EC₅₀) of apigenin on POMC and CART were 0.93 μM and 0.67 μM, respectively, in N29-2 cells, without significant cytotoxic effects. Shortterm food intake was decreased in C57BL/6J mice after an intraperitoneal injection of apigenin (10 mg/kg; p < 0.05). Food intake and body weight gain for 30 days were also reduced slightly in mice fed a high-fat diet containing apigenin (0.05%, w/w; p < 0.05). These results indicate that apigenin increased POMC and CART gene expression in neuronal cells and significantly reduced food intake in C57BL/6 mice, which may be related to the anorexigenic neuropeptides POMC and CART.