ACE2-Ang(1-7)-Mas轴对棕色脂肪功能的作用及其分子调控机制研究

Since brown adipose tissue (BAT) dissipates energy,BAT has garnered attention as a therapeutic intervention for obesity. Some studies have reported that the classical pathway of Renin angiotensin system (RAS) (ACE-AngII-ATR axis) may be related to the function of BAT. Our previous research on the new pathway of RAS (ACE2-Ang(1-7)-Mas axis) found that: under the 4℃ condition, body temperature of ACE2 knockout mice (ACE2-/-) was significantly lower than that of wild-type mice, and ACE2-/-BAT activity was decreased, the protein levels related to mitochondrial function were decrease and BAT showed vacuolation. These results indicated that ACE2-Ang(1-7)-Mas axis may be involved in the regulation of brown fat function. In this project, we intend to construct three types of ACE2 transgenic mice model (drug-treated ACE2-/- mice, wild-type mice transplantation with ACE2-/- BAT and adreno-associated virus (AAV)-ACE2-treated db/db mice) and primary cell level, using molecular and biochemical approaches to investigate the effect of ACE2-Ang(1-7)-MAS axison energy metabolism, to analyze the BAT cell differentiation and cell function, as well as to elucidate the molecular mechanism of ACE2-Ang(1-7)-Mas axis mediated BAT. This study will contribute to analyze the potential anti-obesity effect of ACE2-Ang(1-7)-Mas axis.

提高棕色脂肪的代谢功能可作为预防或治疗肥胖的新途径。有报道，肾素血管紧张素系统（RAS）经典途径ACE-AngII-ATR轴与棕色脂肪功能存在相关性。我们前期对RAS新途径ACE2-Ang(1-7)-Mas轴的研究发现：在低温条件下ACE2基因敲除小鼠（ACE2-/-）体温明显低于野生型小鼠，且其棕色脂肪活性降低、线粒体功能相关蛋白表达量下降及棕色脂肪组织细胞肥大。提示ACE2-Ang(1-7)-Mas轴可能参与棕色脂肪功能调节。我们拟用ACE2-/-小鼠进行Ang(1-7)干预和棕色脂肪移植，并用db/db肥胖伴糖尿病小鼠过表达ACE2等方法研究ACE2-Ang(1-7)-Mas轴对能量代谢、棕色脂肪分化和细胞功能的影响；结合原代细胞水平研究，通过信号通路抑制剂筛选和表达谱检测，阐明其调节棕色脂肪功能的具体作用机制。本研究将有助于解析ACE2-Ang(1-7)-Mas轴潜在的抗肥胖效果。

肥胖在世界范围内均呈现出爆发性流行，发生率呈持续上升的趋势。肥胖与代谢综合症有非常密切的相关性。大量的证据表明，RAS的改变是产生肥胖的一个重要因素，本项目从能量代谢的全新角度出发，关注ACE2-Ang(1-7)-Mas轴对糖脂代谢，特别是对棕色脂肪的影响。着重阐明肥胖过程中ACE2-Ang(1-7)-Mas轴对能量代谢的调控机制，探索ACE2-Ang(1-7)-Mas轴潜在的抗肥胖效果。.本项目利用五种动物模型（ACE2基因敲除小鼠，过表达ACE2腺病毒/Ang-(1-7)干预的DB/DB糖尿病肥胖小鼠，Ang-(1-7)干预高脂诱导的肥胖小鼠和Mas基因敲除小鼠）及原代细胞模型，在棕色脂肪，骨骼肌，肝脏中都证实了ACE2-Ang(1-7)-Mas轴对能量代谢的改善作用：ACE2-Ang(1-7)-Mas轴是棕色脂肪重要调控因子，激活棕色脂肪功能，促进白色脂肪棕色化；Ang(1-7)通过受体Mas通过抑制内质网应激，增强线粒体功能，改善肝脏的能量代谢；ACE2通过调节内质网应激与线粒体保护骨骼肌脂质代谢功能。上述研究全面解析了ACE2-Ang(1-7)-Mas轴对能量代谢的影响，为阐明RAS参与肥胖的调控机制提供了全面的基础研究数据。为肥胖的预防和治疗提供新的药物研发思路和可能的作用靶点。.本项目目前已经发表相关SCI论文四篇，核心期刊3篇，授权发明专利两项，另有一篇综述返回修改，一篇SCI论文在投，部分研究成果获得了2019年度中华医学会科技奖二等奖，2020年度华夏医学会科技奖二等奖。在人才培养方面，协助培养硕士研究生3名，博士研究生2名。