Melanocortin 4 receptors (MC4R) are hypothesized to mediate the CNS actions of leptin to enhance the satiety effects of cholecystokinin (CCK). To further elucidate this mechanism, we confirmed that peripheral administration of CCK-8 is less effective in producing this effect in MC4R-deficient mice (MC4R^-/-). Whereas intraperitoneal (i.p.) CCK-8 at 0.75 nmol/kg lean body mass (lbm) suppressed food intake in wild-type mice, CCK-8 doses of 7.5 nmol/kg lbm were required to attenuate food intake in MC4R^-/- mice. To determine if melanocortin signaling in the hypothalamic paraventricular nucleus (PVN) participates in regulating this CCK satiety response, we administered the MC3/MC4R antagonist, SHU9119 into the PVN of rats prior to i.p. CCK-8 administration. PVN administration of SHU9119 attenuated the ability of CCK-8 to reduce 30-minute food intake by 20%. To determine whether MC4R are expressed by PVN neurons that project directly to hindbrain nuclei involved in the satiety response to i.p. CCK-8, the retrograde tracer fluorescent cholera toxin subunit B was injected into the nucleus tractus solitarius (NTS) of the hindbrain. After four days, labeled PVN neurons were collected by laser capture microdissection and found to express MC4R mRNA by quantitative RT-PCR analysis. These data provide evidence for a neuroanatomical link between hypothalamic melanocortin signaling in the PVN and NTS neurons that regulate food intake. These findings highlight the contribution of melanocortin signaling in the PVN toward regulating the satiety effects of CCK-8 while acknowledging that melanocortin dependent pathways in other brain regions and/or melanocortin independent mechanisms are also important in this mechanism.