Role of Lipid Droplet Proteins in Islet Function in Diabetes and Obesity

脂滴蛋白在糖尿病和肥胖症胰岛功能中的作用

• 批准号: 9405651
• 负责人: Yumi Imai
• 金额: $ 1.31万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2017-02-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9405651
• 关键词: Role; Lipid; Droplet; Proteins; Islet

DESCRIPTION (provided by applicant): The chronic exposure of islets to fatty acids is believed to promote the development of diabetes in obesity by damaging ? cells. Paradoxically, fatty acids also augment insulin secretion acutely. Therefore a better understanding of the regulation of lipid metabolism in islets, especially from spatial and chronological aspects, is critical for the effective strategy to prevent adverse effects of lipid overload. Adipose differentiation-related protein (ADFP), found on the surface of lipid droplets in wide range of cells, is proposed to play a critical role in spatial organization of intracellular lipid metabolism through the interaction with other intracellular organelles such as cell membrane, ER, and mitochondria. The preliminary data from Dr. Imai's laboratory showed that ADFP is increased in human and mouse islets exposed to fatty acids in vivo and ex vivo. Furthermore the reduction of ADFP in insulin secreting cells (MIN6) impairs fatty acid usage and acute augmentation of insulin secretion by fatty acids. Therefore Dr. Imai hypothesizes that ADFP coated lipid droplets in ? cells are critical for the efficient use of fatty acids. They facilitate the generation of fatty acid derived signaling for insulin secretion, while preventing islet dysfunction from lipid overload. The hypothesis will be tested as below. Specific aim 1: Analyze the role of ADFP in the acute augmentation of insulin secretion by fatty acids. The importance of ADFP in this process will be confirmed by reducing ADFP in human islets using adenovirus expressing shRNA, and in vivo using ADFP deficient mice. The mechanisms by which ADFP regulates the generation of signals for insulin secretion will be studied in mouse islets using shRNA for ADFP. Specific aim 2: Analyze the role of ADFP in the development of islet dysfunction in obesity. Since ADFP may promote fatty acid utilization in ? cells, it potentially protects islet from stress of fatty acid overload. Here the efficacy of ADFP upregulation in the prevention of lipid-induced islet dysfunction will be tested using adenovirus in vitro, and using the transgenic approach in vivo. Specific aim 3: Address the roles of islet lipid droplets beyond the regulation of fatty acids-triglycerides metabolism. Recent studies in various cells indicate that the regulatory role played by lipid droplets is not limited to fatty acid metabolism. From several areas where ADFP is implicated, two pathways relevant to islet function will be studied. The change in cholesterol metabolism and eicosanoids production will be analyzed after modulating ADFP levels in MIN6 cells and mouse islets as above. The study will provide innovative, unique information about the spatial and dynamic regulation of lipid metabolism in islets, which will aid the designing of new approaches towards the prevention and treatment of islet dysfunction commonly seen in obesity.

描述（由申请人提供）：胰岛慢性暴露于脂肪酸被认为会通过损害促进肥胖症中糖尿病的发展吗？细胞。矛盾的是，脂肪酸也会急性增强胰岛素分泌。因此，更好地了解胰岛中脂质代谢的调节，尤其是从空间和年代方面的调节，对于防止脂质过载的不利影响的有效策略至关重要。脂肪分化相关蛋白（ADFP）在脂质液滴表面上发现了广泛细胞的表面，被提议通过与其他细胞内细胞器（例如细胞膜ER，ER，ER，ER，ER，ER，ER）相互作用，在细胞内脂质代谢的空间组织中发挥关键作用。和线粒体。 IMAI博士实验室的初步数据表明，在体内和Ex Vivo暴露于脂肪酸的人和小鼠胰岛中，ADFP增加了。此外，胰岛素分泌细胞中ADFP的降低（MIN6）损害了脂肪酸的使用和脂肪酸胰岛素分泌的急性增强。因此，Imai博士假设ADFP涂层的脂质液滴？细胞对于有效使用脂肪酸至关重要。它们促进脂肪酸衍生的信号传导的产生，以进行胰岛素分泌，同时防止脂质过载胰岛功能障碍。该假设将如下检验。具体目标1：分析ADFP在脂肪酸胰岛素分泌急性增强中的作用。通过使用表达shRNA的腺病毒和使用ADFP缺乏小鼠在人类胰岛中，ADFP在此过程中的重要性将得到证实。 ADFP调节胰岛素分泌信号产生的机制将在使用ADFP的SHRNA中研究小鼠胰岛。具体目标2：分析ADFP在肥胖症中胰岛功能障碍发展中的作用。由于ADFP可能会促进脂肪酸的利用？细胞，它有可能保护胰岛免受脂肪酸超负荷的压力。在这里，ADFP上调预防脂质诱导的胰岛功能障碍的功效将在体外使用腺病毒，并在体内使用转基因方法进行测试。特定目标3：解决胰岛脂肪液滴的作用，超出了脂肪酸 - 甘油三酸酯代谢的调节。在各种细胞中的最新研究表明，脂质液滴的调节作用不仅限于脂肪酸代谢。从与ADFP有关的几个领域中，将研究与胰岛功能相关的两个途径。如上所述调节MIN6细胞和小鼠胰岛中的ADFP水平后，将分析胆固醇代谢和类黄花酱的变化。 这项研究将提供有关胰岛中脂质代谢的空间和动态调节的创新，独特的信息，这将有助于设计新方法，以预防和治疗肥胖症中常见的胰岛功能障碍。