Activation of urocortin transport into brain by leptin

There are several transport systems for peptides and polypeptides at the bl ood-brain barrier (BBB) which facilitate the passage of bioactive substance s from blood to brain or from brain to blood. Nonetheless, it would be a no vel concept for one peptide or polypeptide to activate the transport of ano ther peptide with a similar function but unrelated structure. In this study , we report the first observation of such a phenomenon: activation of a uro cortin transport system at the BBB by leptin. Urocortin, a corticotropin-re leasing factor (CRF)-related neuropeptide, is a more potent suppressor of f ood intake than leptin or CRF when injected peripherally. Radiolabeled uroc ortin (I-125-urocortin) was used for these in vivo studies in mice; it rema ined stable and intact during the experimental period. Unlike CRF, urocorti n was not saturably transported out of the brain. There was no substantial entry of I-125-urocortin into brain as determined by sensitive multiple-tim e regression analysis after iv bolus injection. Addition of leptin, however , caused a dose-related increase in the influx of I-125-urocortin and great ly 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 I-125-urocortin into brain was saturable. The results indicate that the presence of leptin contributes to the potent satiety effe cts of urocortin after peripheral administration. Thus, the action of lepti n in the periphery extends beyond its direct passage across the BBB and inv olves acute modulation of an inert transport system. We believe that these findings have broad physiological implications and indicate a unique functi on of the BBB as a regulatory interface. (C) 2000 Elsevier Science Inc. All rights reserved.