Nesfatin-1 is an 82 amino acid peptide that suppresses food intake after intracerebroventricular injection. Nesfatin-1 and its precursor NUCB2 were identified by subtraction cloning in cell lines of both neuronal and adipocytic origin. This provides a strong basis for studies to determine how peripherally derived nesfatin-1 permeates the blood-brain barrier (BBB) to participate in its CNS actions and whether pharmacological delivery by the peripheral route is feasible. In this study, nesfatin-1 remained stable in blood at least 20 min after intravenous injection and permeated the BBB by a non-saturable mechanism. The influx rate of nesfatin-1 after intravenous delivery was 0.27+/-0.11 microl/g-min, and 0.3% of nesfatin-1 reached brain parenchyma 10 min after injection. The lack of saturation of influx was shown by use of excess unlabeled nesfatin-1 in multiple-time regression analysis, capillary depletion, and in situ brain perfusion. After intracerebroventricular injection, nesfatin-1 had a half-time disappearance of 23.8 min, which was not significantly different from that of albumin. This indicates that nesfatin-1 exited the brain by bulk absorption of cerebrospinal fluid without a specific efflux transport system. We conclude that the permeation of nesfatin-1 is a non-saturable process in either the blood-to-brain or brain-to-blood direction. Thus, the limited penetration under physiological conditions does not limit the pharmacological delivery of this satiety peptide as a potential therapeutic agent.