Modulation of feeding-related peptide/protein signals by the blood-brain barrier

The peptide urocortin is a member of the corticotropin-releasing factor (CRF) family and a potent satiety signal to the brain. Urocortin in blood does not reach the brain significantly by itself, but its permeation across the blood-brain barrier (BBB) can be enhanced by leptin. How leptin facilitates the influx of urocortin has not been elucidated. In this study, we tested the hypothesis that leptin activates receptor-mediated endocytosis of urocortin. We measured the kinetics of permeation of radioactively labeled urocortin across the mouse BBB and determined the specific effects of leptin and receptor antibodies. The results show that the influx transfer constant of urocortin was enhanced in the presence of leptin and mediated by CRF-2beta, the specific receptor for urocortin. To determine the specificity of this modulation, the effect of leptin was compared with that of TNFalpha. Both TNFalpha and leptin independently facilitated receptor-mediated transport of urocortin across the BBB. Even though TNFalpha and leptin have similar effects on urocortin transport, leptin did not significantly affect the influx of TNFalpha across the BBB. The results indicate that permeation of ingestive peptides and cytokines across the BBB can be acutely modulated, consistent with a role of BBB in regulating feeding behavior. Thus, sites of action of leptin, urocortin, and TNFalpha exist not only in the brain but also at the BBB where they each control the flow of other ingestive signals to CNS targets.