We previously reported that low dose leptin infusions into the 3^rd or 4^th ventricle that do not effect energy balance when given independently cause rapid weight loss when given simultaneously. Therefore, we tested whether hindbrain leptin enhances the response to forebrain leptin, or whether forebrain leptin enhances the response to hindbrain leptin. Rats received 4^th ventricle infusions of saline, 0.01, 0.1, 0.3 or 0.6 μg leptin/day for 13 days. On days 9 and 13 0.1 μg leptin was injected into the 3^rd ventricle. The injection inhibited food intake for 36 hours in saline infused rats, but for 60 hours in those infused with 0.6 μg leptin/day. Leptin injection increased IBAT temperature in leptin infused, but not saline-infused rats. In a separate experiment rats received 3^rd ventricle infusions of saline, 0.005, 0.01, 0.05 or 0.1 μg leptin/day and 4^th ventricle injections of 1.0 μg leptin on days 9 and 13. Leptin injection inhibited food intake, RER and 14 hour food intake in rats infused with saline or the two lowest doses of leptin. There was no effect with higher dose leptin infusions because food intake, body fat and lean mass were already inhibited. These data suggest that activation of leptin receptors in the hindbrain enhances the response to 3^rd ventricle leptin, whereas activation of forebrain leptin receptors does not enhance the response to 4^th ventricle leptin, consistent with our previous finding that weight loss in rats treated with 4^th ventricle leptin is associated with indirect activation of hypothalamic STAT3.