Fliedner Stephanie, Schulz Carla, Lehnert Hendrik
Department of Endocrinology and Metabolism, Otto-von-Guericke University, Magdeburg, Germany.
Endocrinology. 2006 May;147(5):2088-94. doi: 10.1210/en.2005-1016. Epub 2006 Feb 9.
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 [(125)I]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 [(125)I]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.
瘦素主要由脂肪细胞根据脂肪组织量成比例地合成和分泌。在生理条件下，这种激素通过与中枢神经系统中的神经元相互作用来减少食物摄入并增加产热。然而，瘦素通过血脑屏障进入中枢神经系统的运输是可饱和的，在肥胖状态下，向大脑的反馈信号明显不足。在最近的实验中我们发现，经鼻内（i.n.）给予瘦素可减少大鼠的食物摄入。本研究的目的是探索经鼻内给予的瘦素在脑、血液和外周组织中的分布。将[(125)I]瘦素（0.03、0.1和0.2 mg/kg）应用于雄性Wistar大鼠的鼻孔（每组n = 8），给药后30分钟导致脑内瘦素浓度超过生理水平，下丘脑内的含量（7.3±2.6、5.9±1.6和13.8±5.7 ng/g；P = 0.023；F = 6.157）显著高于脑平均水平（1.2±0.2、3.9±1.0和6.0±1.9 ng/g）。相比之下，枕叶/内嗅皮质中的含量低于脑平均水平，表明通过脑脊液的运输参与较少，而脑脊液暴露的表面本应更有利于这种运输。在采用静脉注射未标记瘦素的实验中，我们能够证明过量的血液瘦素不会减少经鼻内给予的[(125)I]瘦素的脑摄取，这支持了瘦素通过绕过血脑屏障从鼻子直接运输到大脑。因此，本研究清楚地证明了瘦素从鼻子到大脑的快速且高效的运输。
