Control of leptin transport system by LRP

项目摘要 这项资助的总体目标是阐明生理、细胞和分子机制(S) 肥胖相关代谢紊乱中的瘦素抵抗，特别是循环中的瘦素是如何输送到 大脑，长期目标是找到肥胖的新治疗靶点。瘦素是由 脂肪细胞调节食物摄入量和体重。为了实现它的生理动作，它需要 进入大脑。肥胖患者循环中的瘦素水平升高，但脑脊液与血浆瘦素的比率 瘦素仅在中枢给药而不是外周给药时抑制食物摄入，这表明 瘦素进入大脑的转运受损可能是发育过程中瘦素抵抗的一个机制。 肥胖症。然而，在了解瘦素在能量平衡中的作用方面存在着显著的差距 关于脂肪细胞衍生的瘦素如何进入下丘脑神经元的知识。我们现在有 初步数据显示，LRP1或LRP2(低密度脂蛋白受体相关蛋白-1或-2)具有 潜在的瘦素转运体，可通过脉络丛或 柔韧细胞。我们发现脉络丛上皮细胞中LRP1的缺失在以下情况下损害了食物的摄取 瘦素是外周给药。然而，集中给药的瘦素减少了小鼠的食物摄入 脉络丛上皮细胞缺乏LRP1。有趣的是，LRP2在下丘脑中含量丰富 但在下丘脑弓状核(ARH)神经元中不表达。删除 下丘脑区的LRP2，包括柔韧细胞，会导致严重肥胖，并损害瘦素对食物的作用 入口处。因此，我们假设LRP1介导瘦素在血-脑脊液屏障的转运。 LRP2通过伸展细胞将瘦素从脑脊液输送到ARH神经元。在这笔赠款中，目标1 将确定LRP1在调节脉络丛中瘦素运输方面的生理作用。目标2将 阐明LRP2在下丘脑柔韧细胞瘦素运输系统中的生理作用。目标3将 确定LRP2在ARH伸展细胞释放瘦素过程中的生物学功能。要做到这一点， 我们的工作将运用最先进的生物化学、分子、细胞和生理学。 了解大脑对瘦素的动态感知及其对能量代谢的影响的技术。 这些研究为建立以LRP1和LRP2为关键的新范式提供了独特的机会 瘦素介导的代谢决定因素，并可能为肥胖的治疗提供一个新的靶点。

Project Summary The overall goal of this grant is to elucidate the physiologic, cellular, and molecular mechanism(s) underlying leptin resistance in obesity-linked metabolic disorders and, in particular, how circulating leptin is delivered into the brain, with the long-term goal of finding new therapeutic targets for obesity. Leptin is secreted by adipocytes to regulate food intake and body weight. In order to achieve its physiological actions, it needs to enter the brain. In obesity, circulating leptin levels are elevated but the ratio of CSF to plasma leptin is decreased, and leptin only suppresses food intake when administered centrally but not peripherally, suggesting that impaired leptin transport into the brain could be a mechanism for leptin resistance during the development of obesity. However, significant gaps in understanding leptin’s function in energy balance have been the lack of knowledge regarding how adipocyte-derived leptin gain access to the hypothalamic neurons. We now have preliminary data showing LRP1 or LRP2 (low-density lipoprotein receptor-related protein-1 or -2) functions as a potential leptin transporter that can deliver circulating leptin into the brain through the choroid plexus or tanycytes. We found that deletion of LRP1 in the epithelial cells of the choroid plexus impairs food intake when leptin is administered peripherally. However, centrally administered leptin decreases food intake in mice lacking LRP1 in the epithelial cells of the choroid plexus. Interestingly, LRP2 is enriched in hypothalamic tanycytes but is not expressed in the neurons of the arcuate nucleus of the hypothalamus (ARH). Deletion of LRP2 in the hypothalamic area, including tanycytes, causes severe obesity and impairs leptin action on food intake. We thus hypothesize that LRP1 mediates the transport of leptin across the blood-CSF barrier at the choroid plexus, while LRP2 transports leptin from the CSF to ARH neurons via tanycytes. In this grant, Aim 1 will establish the physiological role of LRP1 in regulating leptin transport in the choroid plexus. Aim 2 will elucidate the physiological role of LRP2 in the leptin transport system in hypothalamic tanycytes. Aim 3 will determine the biological function of LRP2 in the delivery of leptin by tanycytes of the ARH. To accomplish this, our work will employ a tour de force of state-of-the-art biochemical, molecular, cellular, and physiological techniques to understand the dynamic sensing of leptin by the brain, and its impacts on energy metabolism. These studies provide a unique opportunity to establish a new paradigm in which LRP 1 and LRP2 are key determinants of leptin-mediated metabolism and may offer a novel target for the treatment of obesity.