Brain Uptake of Intranasally Applied Radioiodinated Leptin in Wistar Rats

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Leptin is mainly synthesized and secreted by fat cells in proportion to adipose tissue mass. Under physiological conditions, this hormone reduces food intake and increases thermogenesis through interactions with neurons in the central nervous system. However, transport of leptin into the central nervous system via the blood-brain barrier is saturable, and in obesity the feedback signal to the brain is markedly insufficient. In recent experiments we have shown, that intranasal (i.n.) delivery of leptin reduces food intake in rats. The aim of the present study was to explore the distribution of i.n. delivered leptin within brain, blood, and peripheral tissues. Application of [125I]leptin (0.03, 0.1, and 0.2 mg/kg) into male Wistar rats’ nares (n = 8 per group) leads to supraphysiological brain leptin concentrations 30 min after application, with contents in the hypothalamus (7.3 ± 2.6, 5.9 ± 1.6, and 13.8 ± 5.7 ng/g; P = 0.023; F = 6.157) being significantly higher than the brain average (1.2 ± 0.2, 3.9 ± 1.0, and 6.0 ± 1.9 ng/g). In contrast, contents in the occipital/entorhinal cortex were lower than the brain average, indicating a minor participation of the transport via cerebrospinal fluid, which would have favored cerebrospinal fluid-exposed surfaces. In experiments employing the application of unlabeled leptin administered iv, we were able to show that excess blood leptin does not diminish brain uptake of i.n. leptin (as indicated by [125I]leptin), supporting a direct transport from nose to brain by circumvention of the blood-brain barrier. This study thus clearly demonstrates a rapid and highly effective transport of leptin from nose to brain.

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