肥大细胞与脂肪细胞互作调控长期高脂饮食小鼠附睾脂肪组织萎缩重构的机制

长期高脂饮食（HFD）小鼠附睾脂肪组织（EAT）萎缩重构与其肝脏并发症的发生紧密相关。我们前期研究发现，在这些小鼠EAT萎缩期间，EAT肥大细胞（MC）数激剧增多，且与EAT重量降低、某些脂肪细胞表型改变、肝重量增加等紧密相关；MC稳定剂DSCG注射能够抑制长期HFD小鼠EAT萎缩和肝重量增加；MC源5-HT能启动EAT脂解作用。这些结果提示，MC可能通过与脂肪细胞互作来调控EAT萎缩重构。本申请书拟进一步明确EAT重构过程中脂肪细胞表型改变、分析EAT萎缩重构期间MC数目变化与脂肪细胞表型改变间的相关性、确认MC对EAT萎缩重构的影响。在此基础上，全面研究MC与脂肪细胞互作调控其表型变化的方式，重点研究MC源5-HT启动脂肪细胞脂解、LDL-C活化MC升高5-HT合成分泌的信号机制。该研究不仅能够丰富免疫细胞调控脂肪组织重构的科学理论，而且能够为相关疾病防治与药物设计提供新的思路。

The atrophic remodeling of epididymal adipose tissue (EAT) can induce the development of liver complications in long-term high-fat diet (HFD)-fed mice. In our prior study, we found that: 1) the number of mast cell (MC) dramatically increased during EAT atrophic remodeling in HFD-fed mice and increased MC number was closely related to the decline in EAT weight, some adipocyte phenotypic changes, and the enhancement of liver weight; 2) daily intraperitoneal (i.p.) injection of the MC stabilizer disodium cromoglycate (DSCG) inhibited EAT atrophy and liver weight enhancement in long-term HFD-fed mice. 3) MC-derived 5-HT promoted EAT lipolysis. These results suggest that MC may regulate EAT atrophic remodeling by the interaction with EAT adipocytes. This grant is intended to further clarify the phenotypic changes of adipocytes, including adipogenesis, adipocyte death, lipogenesis, lipolysis, browning, insulin resistance, and adipokine secretion, during EAT remodeling; to analyze the correlations between the increase in MC number and the phenotypic changes of adipocytes during EAT atrophic remodeling; and to confirm the effects of MC on EAT atrophic remodeling. And then, we shall comprehensively investigate the interactions between MCs and adipocytes, which are implicated in adipocyte phenotypic changes during EAT atrophic remodeling. We will also mainly concern the signal mechanisms of MC-derived 5-HT promoting adipocyte lipolysis and of LDL-C activating MC to induce 5-HT synthesis and secretion. This grant will not only enrich biological theory of immune cells regulating the adipose tissue remodeling, but also suggest the potential of developing new therapies for HFD-induced obesity and associated metabolic diseases.