Banks William A, Niehoff Michael L, Martin David, Farrell Catherine L
GRECC Veterans Affairs Medical Center-St. Louis and Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, 915 N. Grand Blvd., St. Louis, MO 63106, USA.
Brain Res. 2002 Sep 20;950(1-2):130-6. doi: 10.1016/s0006-8993(02)03013-5.
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.
人类肥胖被认为是由对瘦素的抵抗引起的。目前，有证据表明这种抵抗是由瘦素穿过血脑屏障（BBB）的运输受损所致。人们一直认为，瘦素受体的短形式是瘦素转运体，它是产生所有已知瘦素受体的基因的剪接变体，但这方面的证据并不一致。科列茨基大鼠模型应该能就运输是否依赖瘦素受体给出明确答案，因为它不表达任何功能性受体。已发现静脉注射的瘦素在科列茨基大鼠血脑屏障中的运输大幅减少，但仍有残余运输的证据，这使得转运体是基本不存在还是仅仅被血清中高水平的瘦素饱和尚不清楚。在这里，我们使用脑灌注方法来消除血清水平的影响。我们发现，在肥胖的科列茨基大鼠中，静脉注射的瘦素不发生运输，但当使用脑灌注时，运输速率与对照组没有差异。瘦素完全穿过血脑屏障，具有饱和性，并且在脑区中的分布与先前在正常体重小鼠中发现的相同（向海马体和下丘脑的运输最高，额叶皮质最低）。我们得出结论，瘦素转运体及其基因可能尚未被鉴定，并且短形式可能在运输活性的调节中起作用。
