脂肪细胞NAD+水平的调控机制及其在肥胖发生发展中的作用和临床转化研究

Obesity is a chronic metabolic disease which is caused by multiple factors. Our previous screening analysis on the database of the genome-wide expression of human adipose tissue found that expressions of NAMPT and NMRK1 involved in adipose NAD+ synthesis were significantly down-regulated. It has been demonstrated that NAMPT and CD38 are the main synthase and hydrolase of cellular NAD+, respectively，and they coordinately regulate intracellular NAD+ concentration.  In the pre-experiments, we found that CD38 knockout mice remarkably inhibited high-fat diet induced obesity in which their serum triglycerin and cholesterol levels were significantly reduced, and we also observed that deletion of CD38 gene significantly improved mouse glucose tolerance and insulin sensitivity with normal diet or high fat diet. In the present study, we will systematically investigate the roles and mechanisms of CD38 in development of obesity using CD38 conventional knockout mice and adipose specific CD38 knockout mice. Especially, we will focus on exploring the roles of CD38 in insulin tolerance, inflammation of macrophage-mediated inflammation in adipose tissues and adipocyte differentiation. Meanwhile, we will also verify the roles of NAMPT/CD38-mediated NAD+ metabolic pathway in the development of obesity. There is no doubt that our study will provide an insight into the development of new targets or managements for prevention and treatment of obesity.

肥胖是一种多因素引起的慢性代谢性疾病。我们对人脂肪组织全基因组表达数据库的筛查分析发现，在细胞NAD+合成中起关键作用的NAMPT和NMRK1基因在肥胖人群脂肪组织中的表达显著下调。在哺乳类细胞，NAMPT是合成NAD+的重要限速酶，而CD38则是降解NAD+的主要水解酶，两者共同调节细胞内的NAD+水平。我们的预实验发现，CD38全基因敲除鼠明显抑制高脂饮食诱发的肥胖，并伴有血清甘油三脂及胆固醇水平的显著降低，显著改善正常或高脂饮食条件下的葡萄糖耐受及增强对胰岛素的敏感性。本项目利用CD38全基因敲除鼠、脂肪细胞特异性CD38敲除鼠等动物模型，拟从胰岛素耐受、脂肪组织炎症反应及脂肪细胞分化等方面系统研究CD38在肥胖发生中的作用及其机制。同时也将在肥胖人群中验证脂肪组织NAMPT/CD38介导的NAD+代谢途径对肥胖发生的影响，以期为发现干预肥胖发生的新靶点及策略提供依据。

肥胖是一种多因素引起的慢性代谢性疾病。它以体内脂肪细胞的体积增大和细胞数量增加，机体脂肪占体重的百分比异常增高及在某些局部脂肪过多沉积为特点。烟酰胺腺嘌呤二核苷酸(NAD+)作为辅因子以氧化型(NAD+)或还原型(NADH)参与细胞的许多生化反应，在代谢性疾病中具有重要的作用。细胞内的NAD+含量受合成及分解两方面调节。烟酰胺磷酸核糖转移酶（NAMPT）是NAD+补救合成途径的关键限速酶，而CD38是其主要的降解酶。而调控脂肪细胞NAD+代谢的这两个关键酶在肥胖中的作用尚未见报道。因此，本课题重点探讨NAMPT和CD38调控的脂肪细胞NAD+代谢途径在肥胖的发生发展过程中的作用及其机制，为肥胖的防治提供了新的方向。通过项目的实施，我们利用整体动物模型和体外细胞实验证明了以下几点：1）NAD+代谢通路与肥胖的发生密切相关，NAMPT在肥胖人群及高脂饮食喂养小鼠的白色脂肪组织（WAT）中表达下降， 而CD38在高脂饮食诱导的肥胖小鼠WAT中表达上调 ；2）NAMPT抑制剂（FK866）可明显促进WAT脂质合成，进而加重高脂饮食诱导的肥胖，相反，CD38基因缺失可显著抑制WAT脂质合成，进而抑制高脂饮食诱导的肥胖；3）CD38缺失可明显抑制脂肪细胞分化及脂质合成过程，进而抑制肥胖，其机制可能与其调节脂肪细胞NAD+/Sirt1/PPARγ信号通路活性有关。我们的研究阐述了调控脂肪细胞NAD+代谢对肥胖的作用及其机制，同时也发现NAD+代谢的关键酶NAMPT及CD38在其他代谢性疾病如非酒精性脂肪肝和糖尿病心肌病等具有保护作用。我们的研究结果表明通过调控脂肪细胞的NAD+代谢具有明确的抗肥胖新功能，从而为抗肥胖药物开发提供了新靶点。