Control of leptin transport system by LRP

LRP 控制瘦素转运系统

• 批准号: 10620359
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620359
• 关键词: Adipocytes; Anorexia; Area; Biochemical; Biological Process; Blood; Body Weight; Brain; Calcium Oscillations; Cell Communication; Cell Line; Cell membrane; Cerebrospinal Fluid; Circulation; 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; LDL-Receptor Related Protein 2; Lateral; Leptin; Leptin resistance; Link; Lipoprotein Receptor; Mediating; Metabolic Diseases; Metabolism; Molecular; Morbid Obesity; Mus; Neuroglia; Neurons; Obesity; Peripheral; Phosphorylation; Physiological; Plasma; Play; Proteins; 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 这项资助的总体目标是阐明潜在的生理、细胞和分子机制， 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传递到 大脑，长期目标是寻找肥胖症的新治疗靶点。瘦素是由 脂肪细胞来调节食物摄入和体重。为了实现其生理作用，它需要 进入大脑。在肥胖症中，循环瘦素水平升高，但CSF与血浆瘦素的比率降低。 减少，瘦素只抑制食物摄入时，集中管理，但不外周，这表明 瘦素向大脑的转运受损可能是发育过程中瘦素抵抗的一种机制， 肥胖症。然而，在理解瘦素在能量平衡中的功能方面， 关于脂肪细胞来源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，LRP 1或LRP 2（低密度脂蛋白受体相关蛋白-1或-2）作为一种蛋白， 潜在的瘦素转运蛋白，其可以通过脉络丛将循环瘦素递送到大脑中，或 伸长细胞我们发现脉络丛上皮细胞中LRP 1的缺失会损害食物摄入， 瘦素是外周给药的。然而，在小鼠中，集中施用瘦素减少食物摄入 在脉络丛的上皮细胞中缺乏LRP 1。有趣的是，LRP 2在下丘脑中富集， 但在下丘脑弓状核（ARH）的神经元中不表达。删除 下丘脑区域（包括伸长细胞）中的LRP 2导致严重肥胖并损害瘦素对食物的作用 摄入因此，我们假设LRP 1介导瘦素通过血-CSF屏障的转运， LRP 2通过伸展细胞将瘦素从CSF转运到ARH神经元。在这份补助金中，目标1 将确立LRP 1在调节脉络丛中瘦素转运中的生理作用。目标2将 阐明LRP 2在下丘脑伸长细胞瘦素转运系统中的生理作用。目标3将 确定LRP 2在ARH的伸长细胞递送瘦素中的生物学功能。为了实现这一点， 我们的工作将采用最先进的生物化学，分子，细胞和生理学的力量 技术，以了解瘦素的大脑的动态传感，以及它对能量代谢的影响。 这些研究提供了一个独特的机会，以建立一个新的范式，其中LRP 1和LRP 2是关键 瘦素介导的代谢的决定因素，并可能提供一个新的治疗肥胖症的目标。

项目成果

Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function.

• DOI: 10.1038/s42255-021-00432-5
• 发表时间: 2021-08
• 期刊: Nature metabolism
• 影响因子: 20.8
• 作者: Duquenne M;Folgueira C;Bourouh C;Millet M;Silva A;Clasadonte J;Imbernon M;Fernandois D;Martinez-Corral I;Kusumakshi S;Caron E;Rasika S;Deliglia E;Jouy N;Oishi A;Mazzone M;Trinquet E;Tavernier J;Kim YB;Ory S;Jockers R;Schwaninger M;Boehm U;Nogueiras R;Annicotte JS;Gasman S;Dam J;Prévot V
• 通讯作者: Prévot V