Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats
Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats
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DOI：
10.2337/diabetes.49.7.1219
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发表时间：
2000-07-01
期刊：
影响因子：
7.7
通讯作者：
Poduslo, JF
中科院分区：
文献类型：
--
作者：
Burguera, B;Couce, ME;Poduslo, JF
瘦素通过作用于大脑对食物摄入和能量消耗的调节发挥重要作用。瘦素由脂肪细胞分泌到血流中，并且必须进入大脑中参与调节能量平衡的特定区域。其作用是通过与主要在下丘脑表达但也存在于其他大脑区域的受体相互作用介导的。为了到达这些目标区域，瘦素很可能需要穿过血脑屏障 (BBB)。在这项研究中，我们通过对不同脑区血管床中瘦素占据的残余血浆体积（V-p）进行校正后量化通透系数表面积（PS）乘积，比较了纯合瘦（FA/FA）、高脂饮食诱导（HFD）肥胖大鼠（高脂饮食的FA/FA大鼠）和遗传性肥胖fa/fa Zucker大鼠的BBB处瘦素的通透性。采用静脉推注技术在插管的臂静脉和动脉中使用2种碘同位素（I-125和I-131）放射性碘化瘦素来分别测定PS和V-p值。瘦 FA/FA 大鼠 BBB 处瘦素的 PS 范围为皮质处的 11.0 +/- 1.6 至 14.8 +/- 1.4 x 10(-6) ml 。 g(-1) 。 ml(-1) 位于下丘脑后部。 HFD 肥胖 FA/FA 和肥胖 fa/fa 大鼠中瘦素的 PS 比瘦 FA/FA 大鼠低 3.0 至 4.0 倍。研究的 3 组之间的 V-p 值没有显着差异。摄取 60 分钟后，对放射性碘化瘦素进行 SDS-PAGE 分析，结果显示 8 个不同的大脑区域具有完整的蛋白质。与瘦 FA/FA 大鼠相比，两个肥胖大鼠组的血浆瘦素水平均显着升高。 3组大鼠脑脊液中瘦素水平无显着差异。这些发现强烈表明 BBB 中的瘦素受体 (OB-R) 很容易饱和。肥胖个体中 BBB OB-R 的饱和度可以解释本研究中描述的瘦素转运到大脑中的缺陷。
Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin is secreted by adipocytes into the bloodstream and must gain access to specific regions in the brain involved in regulating energy balance. Its action is mediated by interaction with a receptor that is mainly expressed in the hypothalamus but is also present in other cerebral areas. To reach these target areas, leptin most likely needs to cross the blood-brain barrier (BBB). In this study, we compared the permeability of leptin at the BBB in homozygous lean (FA/FA), high-fat diet-induced (HFD) obese rats (FA/FA rats on a high-fat diet), and genetically obese fa/fa Zucker rats by quantifying the permeability coefficient surface area (PS) product after correction for the residual plasma volume (V-p) occupied by leptin in the vessel bed of different brain regions. The intravenous bolus injection technique was used in the cannulated brachial vein and artery using leptin radioiodinated with 2 isotopes of iodine (I-125 and I-131) to separately determine the PS and V-p values. The PS for leptin at the BBB in lean FA/FA rats ranged from 11.0 +/- 1.6 at the cortex to 14.8 +/- 1.4 x 10(-6) ml . g(-1) . ml(-1) at the posterior hypothalamus. The PS for leptin in HFD obese FA/FA and obese fa/fa rats ranged from 3.0- to 4.0-fold lower than in lean FA/FA rats. The V-p values were not significantly different among the 3 groups studied. SDS-PAGE analysis of the radioiodinated leptin after 60 min of uptake revealed intact protein in the 8 different brain regions. Plasma leptin levels were significantly higher in both obese rat groups compared with those in lean FA/FA rats. Leptin levels in cerebrospinal fluid were not significantly different among the 3 groups of rats. These findings strongly suggest that the leptin receptor (OB-R) in the BBB can be easily saturated. Saturation of the BBB OB-R in obese individuals would explain the defect in leptin transport into the brain described in this study.