Objective To investigate the mechanism of hyperphagia and obesity induced by bilateral lesions of the hypothalamic paraventricular nuclei (PVN). Methods Wistar male rats (36 rats) were used. After bilateral electrolytic lesions of the PVN, we measured the effects of ghrelin, melanotan-II (MT-II, a synthetic structural homologue of alpha-melanocyte-stimulating hormone, α-MSH) and cholecystokinin8 (CCK-8) on food intake in rats with PVN lesions. Results After bilateral electrolytic lesions of the PVN, the body weight and food intake were significantly increased, showing hyperphagia and obesity. After 1 week of bilateral electrolytic lesions of the PVN, the rats were given ghrelin and CCK-8 intraperitoneally, or intracerebroventricular infusion of MT-II. We measured the cumulative food intake (FI) for 4 hours after ghrelin injection in rats fed ad lib, and the changes in FI at 15min, 30min, 1 hour and 2 hours after administration of MT-II and CCK-8 in rats fasted for 24 hours. Ghrelin significantly increased cumulative FI, with maximal response 3 hours and 4 hours after injection, and at these times, the FI of PVN-lesioned rats was greater than that of sham-operated rats. MT-II decreased FI in shamoperated, but not in PVNlesioned rats. CCK-8 decreased FI at each time point in all groups, there was no difference between PVN-lesioned and sham-operated rats. Conclusion The hyperphagia and obesity induced by PVN lesions might be related to an increased orexigenic action of ghrelin d