Kastin A J, Akerstrom V, Pan W
VA Medical Center and Tulane University School of Medicine, 1601 Perdido Street, New Orleans, LA 70112-1262, USA.
Peptides. 2000 Dec;21(12):1811-7. doi: 10.1016/s0196-9781(00)00349-1.
There are several transport systems for peptides and polypeptides at the blood-brain barrier (BBB) which facilitate the passage of bioactive substances from blood to brain or from brain to blood. Nonetheless, it would be a novel concept for one peptide or polypeptide to activate the transport of another peptide with a similar function but unrelated structure. In this study, we report the first observation of such a phenomenon: activation of a urocortin transport system at the BBB by leptin. Urocortin, a corticotropin-releasing factor (CRF)-related neuropeptide, is a more potent suppressor of food intake than leptin or CRF when injected peripherally. Radiolabeled urocortin ((125)I-urocortin) was used for these in vivo studies in mice; it remained stable and intact during the experimental period. Unlike CRF, urocortin was not saturably transported out of the brain. There was no substantial entry of (125)I-urocortin into brain as determined by sensitive multiple-time regression analysis after iv bolus injection. Addition of leptin, however, caused a dose-related increase in the influx of (125)I-urocortin and greatly facilitated its entry into brain parenchyma; this effect disappeared at higher doses of leptin. Moreover, in the presence of an activating dose of leptin, the entry of (125)I-urocortin into brain was saturable. The results indicate that the presence of leptin contributes to the potent satiety effects of urocortin after peripheral administration. Thus, the action of leptin in the periphery extends beyond its direct passage across the BBB and involves acute modulation of an inert transport system. We believe that these findings have broad physiological implications and indicate a unique function of the BBB as a regulatory interface.
血脑屏障（BBB）存在多种肽和多肽转运系统，可促进生物活性物质从血液进入大脑或从大脑进入血液。然而，一种肽或多肽激活另一种功能相似但结构无关的肽的转运，这将是一个全新的概念。在本研究中，我们首次报道了这样一种现象：瘦素激活血脑屏障处的尿皮质素转运系统。尿皮质素是一种与促肾上腺皮质激素释放因子（CRF）相关的神经肽，在外周注射时，它比瘦素或CRF更有效地抑制食物摄入。放射性标记的尿皮质素（（125）I-尿皮质素）用于小鼠的这些体内研究；在实验期间它保持稳定且完整。与CRF不同，尿皮质素不会从大脑中被饱和转运出去。静脉推注后通过灵敏的多次回归分析确定，（125）I-尿皮质素没有大量进入大脑。然而，添加瘦素会导致（125）I-尿皮质素的流入呈剂量相关增加，并极大地促进其进入脑实质；在更高剂量的瘦素作用下这种效应消失。此外，在有激活剂量的瘦素存在时，（125）I-尿皮质素进入大脑是可饱和的。结果表明，瘦素的存在有助于外周给药后尿皮质素产生强大的饱腹感效应。因此，瘦素在外周的作用不仅限于其直接穿过血脑屏障，还涉及对一个惰性转运系统的急性调节。我们认为这些发现具有广泛的生理学意义，并表明血脑屏障作为一个调节界面具有独特功能。
