细胞间粘附分子-1在脂肪前体细胞识别和分化调节中的作用及机制

The enhanced white adipose tissue mass related to obesity is the result of both hyperplasia and hypertrophy of adipocytes. In vitro studies using well-established preadipocyte cell lines have illustrated a transcriptional cascade that is required for adipogenesis, however, the mechanisms dominating adipocyte number are elusive as the limitation in identifying the physiological adipocyte progenitor cells in vivo. Our previous studies found that intercellular adhesion molecule-1 (ICAM-1) deficiency in stromal cells promoted the development of high fat diet induced obesity. The increased adipose tissue is regulated by hyperplasia. By sorting and analyzing the adipocyte progenitor cells in stromal vascular fraction of adipose tissue, we found that ICAM-1+ cells are apt to differentiate into adipocytes. In vivo tracing experiments demonstrated that ICAM-1+ cells developed into mature adipocytes during obesity, suggesting that ICAM-1 is the marker for committed preadipocytes. Interestingly, we found that ICAM-1 expression is gradually decreased during the adipogenesis. Also, ICAM-1 deficiency in preadipocytes promoted their terminal differentiation. Thus, we hypotheses that ICAM-1 is a marker of committed preadipocytes and negatively regulates the terminal differentiation of preadipocytes, thereby deciding the adipose tissue status and regulating the development of obesity. By employing tracing mice and gene knockout mice, we will explore the role of ICAM-1 in identifying preadipocytes in the development of adipose tissue during nascent stage and the reconstruction of adipose tissue during obesity. We will further elucidate the mechanisms of ICAM-1 in regulating the differentiation of preadipocytes. We believe that the completion of this study will provide not only the critical information for understanding of the identification of preadipocytes, but also for finding new targets to prevent and treat obesity.

白色脂肪组织增大与肥胖密切相关，主要归咎于脂肪细胞数目增多和体积增大。尽管大量体外实验证明成脂分化的分子机制，但是体内脂肪前体细胞的分子标志及其分化调节尚未阐明。我们发现，细胞间粘附分子-1（ICAM-1）在基质细胞中缺失时显著促进肥胖发生，并且脂肪组织增大依赖于脂肪细胞数目增加，提示脂肪前体细胞分化增多。通过分析脂肪组织中富含脂肪前体细胞的基质血管成分，研究发现ICAM-1+细胞更易于分化为脂肪细胞。体内示踪实验发现肥胖过程中ICAM-1+细胞分化为成熟脂肪细胞，提示ICAM-1是脂肪前体细胞的分子标志。此外，在成脂分化过程中ICAM-1表达逐渐降低，并且负向调节脂肪前体细胞的终末分化。相关研究目前尚无报道。本项目将利用示踪小鼠、基因缺失小鼠，在脂肪组织发育和病理性重塑中研究ICAM-1在脂肪前体细胞识别及其分化调控中的作用，拓展我们对脂肪前体细胞特性及其功能调节的认识。

脂肪细胞是控制能量平衡和机体脂类稳态的核心。脂肪组织以脂滴的形成储存过多的能量是生物进化中重要的适应性过程。然而，过多脂肪组织积聚引起肥胖的发生则是2型糖尿病、胰岛素抵抗等代谢类疾病发生的危险因素。白色脂肪组织过度增加主要归咎于脂肪细胞数目增多和体积增大。尽管大量体外实验证明成脂分化的分子机制，但是体内脂肪前体细胞的分子标志及其分化调节尚未阐明。本项目围绕科学假设“ICAM-1是脂肪前体细胞的分子标志，并且负向调节脂肪前体细胞的终末分化，决定脂肪组织状态，调控脂肪组织发育和重塑”进行研究，并按原计划完成。研究发现：1.作为脂肪细胞源泉的间充质干细胞的异质性特征和形成机制；2.发现ICAM-1在脂肪前体细胞中的特异性表达，明确其在脂肪前体细胞识别中的作用；3.明确ICAM-1+脂肪前体细胞的组织定位及其与免疫细胞之间的相互作用；4.解析了ICAM-1负向调控成脂分化的核心机制，靶向调控关键分子在脂肪组织重塑中的作用；5.发现硬酯酰辅酶A去饱和酶1缺失促进脂肪前体细胞分化为米色脂肪，提高机体产热，对抗肥胖及其相关胰岛素抵抗；6.明确琥珀酸累积直接提高线粒体复合物2活性，促进米色脂肪新生，有利于对抗肥胖及相关代谢类疾病。发表带本项目资助论文10篇，主要发表在PNAS、Cell Metabolism、Science Advances、Cell Death and Differentiation、Cell Death and Disease等杂志，申请中国专利和国际专利各1项。本项目的研究拓展了我们对脂肪前体细胞生物学特性和功能的认识，也为肥胖及其相关代谢类疾病的临床诊治提供有价值的新靶标。