Leptin transport across the blood-brain barrier of the Koletsky rat is not mediated by a product of the leptin receptor gene

Obesity in humans is thought to be caused by a resistance to leptin. Currently, the evidence suggests that this resistance is caused by an impaired transport of leptin across the blood-brain barrier (BBB). It has been assumed that the short form of the leptin receptor, which is a splice variant of the gene which produces all known leptin receptors, is the leptin transporter, but evidence for this is mixed. The Koletsky rat model should provide a clear answer as to whether transport is dependent on leptin receptors as it does not express any functional receptors. The transport of intravenous leptin across the BBB of the Koletsky rat has been found to be greatly reduced, but evidence for a residual of transport makes it unclear whether the transporter is essentially absent or simply saturated by the high levels of leptin in the serum. Here we used the brain perfusion method to negate the influence of serum levels. We found that, whereas no transport of intravenous leptin occurred in the obese Koletsky, the rate of transport was no different from controls when brain perfusion was used. Leptin was transported completely across the BBB, was saturable, and had the same distribution among brain regions as previously found in normal weight mice (highest transport into the hippocampus and hypothalamus, lowest in the frontal cortex). We conclude that a leptin transporter and possibly its gene have yet to be identified and that the short form likely plays a role in the modulation of transport activity. (C) 2002 Published by Elsevier Science B.V.