脂肪细胞源性外泌体的分泌调节和代谢功能

The epidemic of obesity and its associated metabolic disorders have drawn extensive attention to the biology and physiology of adipose tissue. In addition to its role as the main storage depot for triglycerides, adipose tissue has been recognized as an active endocrine organ that regulates whole body energy homeostasis. An increasing number of adipocyte-derived secretory factors (e.g. adipokines) have been identified to modulate a number of signaling pathways and metabolism in target tissues. Recent studies indicate that this communication may also involve adipocyte-derived exosomes. Exosomes originate in multivesicular bodies (MVBs) and are secreted through an exocytosis pathway. They host a variety of bioactive molecules which include growth factors and their receptors, signaling molecules, as well as nucleic acids (DNA, mRNA, and micro-RNA (miRNA)), indicating their potential for regulation of a broad array of intercellular communication. However, the metabolic regulation of secretion of these exosomes remains unexplored. Potential functions of adipocyte exosomes on metabolism of peripheral tissues are also not clear. Our preliminary data demonstrated that FA release upon lipolytic stimulation induces exosome secretion from adipocytes. Accordingly, this proposal is designed to study how FA and insulin signaling pathway may regulate adipocyte exosome secretion. Findings will be followed by studies to perform comparative analyses of proteome, lipidome, transcriptome and miRNAs in adipocyte-derived exosmes from diet-induced obese mouse models and mouse models with altered adipocyte glucose and lipid metabolism. We will further test whether adipocyte exosome secretion contributes to the development of insulin resistance in obesity. Completion of this study will provide a novel database that is currently not available and that will be helpful to researchers interested in adipose secretions and provide proof of concept information on the feasibility of using exosomes as therapeutic tools to treat metabolic disorders.

肥胖症及其相关的代谢综合征的流行已经引起越来越多的脂肪组织生物学和生理学功能的研究。这些研究表明脂肪组织不仅储存与释放能量，而且还是一个重要的内分泌器官，其中包含众多生物活性分子的外泌体也参与脂肪组织和外周靶器官间的信息传递。然而，这些外泌体形成和分泌是如何调节及其代谢功能尚需深入的研究。本项目拟结合以质谱为手段的脂组学技术，脂肪细胞生物学技术，和调节脂肪细胞糖脂代谢的转基因小鼠模型，多层次探讨脂肪细胞源性外泌体的分泌调控和代谢功能的机制。我们将率先研究糖脂代谢及胰岛素信号通路是如何调节外泌体的分泌，并对不同来源的脂肪细胞外泌体的各种组分进行全面的比较分析；并且进一步检测脂肪细胞外泌体是否参与了由肥胖引起的胰岛素抵抗。这些研究将为肥胖症和II型糖尿病的病理生理学提供崭新的知识并有助于阐明人体代谢疾病中外泌体作用的机制。

肥胖症和体重增加是引起代谢综合征的主要原因，因而引起了科学工作者对脂肪组织生物学和生理学功能的广泛关注。近年研究表明脂肪组织的不仅储存能量并根据机体需要释放能量物质游离脂肪酸，而且还是一个重要的调节全身糖脂，及能量平衡的内分泌器官。我们的研究目标就是进一步了解脂肪组织作为内分泌器官的作用机制，为治疗肥胖及其相关代谢综合征提供新的靶标。..本研究计划以项目负责人团队多年的脂质代谢研究成果为基础，以CD36和FA2H为主要蛋白研究对象，以外泌体为载体，应用细胞和小鼠模型，以及临床样品分析，来研究作为内分泌器官的脂肪组织调节外周代谢器官的可能分子机制。..本研究的成果主要有：1）白色脂肪细胞，棕色脂肪细胞以及巨噬细胞均是脂肪组织外泌体的重要来源，所分泌外泌体中含有丰富的活性核酸，脂分子和蛋白质。外泌体是脂肪组织中脂肪细胞与巨噬细胞协同作用的重要交流介质，共同对外周代谢器官的代谢调节；2）脂肪酸通过其转运蛋白CD36通过Fyn激酶来调节在细胞胰岛素信号传导中发挥重要作用的连接蛋白IRS1的泛素化和降解， CD36/Fyn/IRS1复合体的形成是CD36影响IRS1降解的关键。3）单甲基支链脂肪酸由支链氨基酸的代谢产物（短链支链脂肪酸）为引物合成而来，肥胖人群脂肪组织中支链脂肪酸含量相对正常体重人群脂肪组织明显减少，并且在减肥后，水平得到恢复，更有意思的是脂肪组织中支链脂肪酸含量与个体的胰岛素灵敏度相关；4）脂肪细胞源性的生物活性脂类可能参与调节禁食减肥期间脂肪降解导致的与促炎症激活有关脂肪组织巨噬细胞的聚集。此招募有助于限制局部脂质浓度和脂毒性的增加，而不像肥胖症白色脂肪组织中慢性激活的巨噬细胞的聚集。..总的来说，本研究计划探讨了脂肪组织中脂肪细胞与巨噬细胞协同作用对外周代谢器官的调节作用，研究成果帮助了解肥胖患者中脂肪组织过度扩张引起的胰岛素抵抗性和糖尿病的可能机制，为治疗代谢病的药物开发提供新的可能靶点。