Control of leptin transport system by LRP

LRP 控制瘦素转运系统

• 批准号: 10396523
• 负责人: YOUNG-BUM KIM
• 金额: $ 49.44万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396523
• 关键词: Adipocytes; Anorexia; Area; Biochemical; Biological Process; Blood; Blood Circulation; Body Weight; Brain; Calcium Oscillations; Cell Communication; Cell Line; Cell membrane; Cerebrospinal Fluid; Complex; Coupled; Data; Development; Eating; Endocytosis; Energy Metabolism; Epithelial Cells; Genes; Goals; Grant; Hormones; Human; Hyperphagia; Hypothalamic structure; Impairment; Injections; Knock-out; Knowledge; LDL-Receptor Related Protein 1; Lateral; Lead; Leptin; Leptin resistance; Link; Mediating; Metabolic Diseases; Metabolism; Molecular; Morbid Obesity; Mus; Neuroglia; Neurons; Obesity; Peripheral; Phosphorylation; Physiological; Plasma; Play; Regulation; Resistance; Role; Signal Transduction; Slice; Structure of choroid plexus; Structure of nucleus infundibularis hypothalami; System; Techniques; Third ventricle structure; Weight Gain; Work; energy balance; genetic variant; human disease; in vivo; leptin receptor; median eminence; new therapeutic target; novel; novel therapeutic intervention; obesity development; obesity treatment; reduced food intake; response; transcytosis; uptake

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.

项目摘要 该赠款的总体目标是阐明基础的生理，细胞和分子机制 肥胖连接代谢性疾病中的瘦素耐药性，尤其是如何循环瘦素递送到 大脑，其长期目标是为肥胖症找到新的治疗靶标。瘦素分泌 脂肪细胞调节食物摄入和体重。为了实现其身体行动，它需要 进入大脑。在目标上，循环瘦素水平升高，但CSF与血浆瘦素的比率为 减少，瘦素仅在中央施用时抑制食物摄入量 瘦素进入大脑的障碍可能是发育过程中瘦素耐药性的机制 肥胖。但是，理解瘦素在能量平衡中的功能的显着差距是缺乏 关于脂肪细胞衍生的瘦素如何获得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）作为一种 潜在的瘦素转运蛋白可以通过脉络丛或 tanycytes。我们发现脉络丛上皮细胞中LRP1的缺失会损害食物的摄入量 瘦素是外围给药的。但是，中央施用的瘦素会降低小鼠的食物摄入量 在脉络丛的上皮细胞中缺乏LRP1。有趣的是，LRP2富含下丘脑 tanycytes，但在下丘脑（ARH）的弧形核的神经元中未表达。删除 下丘脑区域的LRP2（包括tanycytes）会导致严重的肥胖症并损害瘦素对食物的作用 进气。因此，我们假设LRP1介导了瘦素在血液-CSF屏障上的转运 脉络丛，而LRP2通过tanycytes将瘦素从CSF转移到ARH神经元。在这笔赠款中，目标1 将确定LRP1在控制脉络丛中瘦素转运中的身体作用。 AIM 2意志 阐明了下丘脑tanycytes中LRP2在瘦素转运系统中的身体作用。目标3意志 确定LRP2在通过ARH的Tanycytes传递瘦素中的生物学功能。为此， 我们的工作将采用最先进的生化，分子，细胞和生理的巡回赛。 了解大脑对瘦素的动态敏感性及其对能量代谢的影响。 这些研究提供了一个独特的机会来建立一个新的范式，其中LRP 1和LRP2是关键 瘦素介导的新陈代谢的决定因素，并可能为肥胖治疗提供新的靶标。