Diurnal variation of leptin entry from blood to brain involving partial saturation of the transport system

The blood-brain barrier (BBB) regulates the amount of peripherally produced leptin reaching the brain. Knowing that the blood concentration of leptin has a circadian rhythm, we investigated whether the influx of leptin at the BBB followed the same pattern in three main sets of experiments. (a): The entry of I-125-leptin from blood to brain was measured in mice every 4 h, a s indicated by the influx rate of I-125-leptin 1-10 min after an iv bolus i njection. The blood concentration of endogenous leptin was measured at the same times. Blood leptin concentrations were higher at night and early morn ing (peak at 0800 h) and lower during the day (nadir at 1600 h). By contras t, the influx of I-125-leptin was fastest at 2000 h and slowest at 0400 h. Addition of unlabeled leptin (1 mug/mouse) significantly decreased the infl ux rate of I-125-leptin at all time points, indicating saturability of the transport system. The unlabeled leptin also abolished the diurnal variation of the influx of I-125-leptin. (b): The entry of I-125-leptin into spinal cord was faster than that into brain and showed a different diurnal pattern . The greatest influx occurred at 2400 h and the slowest at 0800 h. In spin al cord, unlike brain, unlabeled leptin (1 mug/mouse) neither inhibited the influx of I-125-leptin nor abolished the diurnal rhythm. (c): Higher conce ntrations of unlabeled leptin (5 mug/mouse) inhibited the uptake of I-125-l eptin in spinal cord as well as in brain, but not in muscle. This experimen t measured uptake 10 min after iv injection at 0600 h (beginning of the lig ht cycle) and 1800 h (beginning of the dark cycle). Thus, influx of I-125-l eptin into the CNS shows diurnal variation, indicating a circadian rhythm i n the transport system at the BBB, saturation of the leptin transport syste m shows differences between the brain and spinal cord, and blood concentrat ions of leptin suggest that partial saturation of the transport system occu rs at physiological concentrations of circulating leptin, contributing to t he differing diurnal patterns in brain and spinal cord. Together, the resul ts show that the BBB is actively involved in the neuroendocrine regulation of feeding behavior. (C) 2001 Elsevier Science Inc. All rights reserved.