CD146作为ANGPTL2的受体促进肥胖发生的功能与机制研究

肥胖及其并发症日趋成为威胁人类健康的重大问题。目前研究主要集中在探讨胞内转录因子和胞外细胞因子的功能，而对衔接二者膜受体的研究很少。ANGPTL2是促进肥胖及并发症的重要脂肪因子，脂肪细胞上是否存在其受体及其促进肥胖的分子机制一直是该领域悬而未决的科学问题。最近，申请人发现膜受体分子CD146在人和鼠的脂肪细胞上高表达，继而发现ANGPTL2与CD146在脂肪细胞上直接结合，而这种结合被CD146抗体抑制。全身或脂肪细胞特异敲除CD146能抑制肥胖及并发症。据此，申请人提出CD146是介导ANGPTL2向脂肪细胞内传递信号，从而促进肥胖及并发症的关键膜受体。为此，本项目拟通过多种CD146敲除小鼠模型并结合临床样本，系统研究ANGPTL2/CD146对脂肪细胞分化和脂质代谢的影响及其促进肥胖的分子机制，探讨CD146抗体治疗肥胖的可行性，以期为肥胖发生机制提供新思想，为肥胖治疗提供新靶标。

Obesity and its complications are increasingly becoming a major threat to human health. At present, the research on obesity mainly focuses on intracellular transcription factors and extracellular cytokines, and there is still a lack of membrane receptor molecules which can be targeted to treat obesity. For example, ANGPTL2 is one of the important adipocytokines, which promotes obesity and its complications. However, the mechanism that ANGPTL2 promotes obesity is not clear. Recently, when we study the function of CD146 which is high expressed in adipocyte, we find that: ANGPTL2 interacts with CD146 directly in adipocytes, and anti-CD146 antibody blocked CD146-ANGPTL2 interaction. Systemic or adipose tissue-specific knockout of CD146 protects mice from obesity and related detrimental effects. Thus, we propose that CD146 is the key receptor for transmitting ANGPTL2 signaling from extracellular to intracellular in the development of obesity and related diseases. In this study, we will take advantage of various CD146 knockout mouse models and clinical samples to study the function and molecular mechanism of ANGPTL2/CD146 in promoting obesity systematically and the therapy effects of targeting CD146 in obesity. This study will provide a new molecular mechanism for obesity and provide a new target for obesity treatment.