In 1997, two publications showed that animals with diet-induced obesity went though a phase when they no longer responded to leptin given peripherally but still responded to leptin given directly into the brain.9,10 This was evidence not only that leptin was crossing the BBB in ineffective amounts, but also there existed a phase in which resistance at the BBB (termed peripheral resistance) was functionally dominant to resistance at the receptor/postreceptor level (termed central resistance). This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.