Leptin is a 17-kDa protein secreted by fat cells that regulates body adiposity by crossing the blood-brain barrier (BBB) to affect feeding and thermogenesis. Obese human and rodent models of dietary obesity have shown decreased sensitivity to blood-borne leptin, postulated to be due to impaired transport of leptin across the BBB. We show here that the transport rate of leptin across the BBB is reduced about 2/3 in 12-month-old obese CD-1 mice. In a follow-up study, a perfusion method was used that replaced the blood with a buffer containing low concentrations of radioactive leptin. Obese mice still had lower rates of transport into the brain than lean mice, which shows that the reduction in transport rate associated with obesity is not due simply to saturation of transporter secondary to higher serum leptin levels as has been thought, but to a decreased capacity of the BBB to transport leptin. This suggests a new model for obesity in which a defect in the BBB transport of leptin into the CNS underlies the insensitivity to leptin and leads to obesity.