脂肪干细胞衰老造成的分化受阻是引发脂肪细胞过度膨大和肥大型肥胖个体胰岛素抵抗的可能诱因，深入研究其分子病理机制意义重大。预实验中我们发现肥大型肥胖小鼠皮下脂肪间充质干细胞（ADSCs）出现衰老表型和内质网应激（ERS）显著升高的现象，与两者密切相关的转录因子NRF2的活性和基因Mfn2相对表达量显著下调，且Mfn2启动子区存在潜在的NRF2转录结合位点。但这些异常信号对ADSCs衰老的影响并不明确。本项目将通过CHIP-seq实验比较肥大型肥胖与正常小鼠皮下ADSCs中NRF2对Mfn2转录调控的差异；通过体外基因干扰和超表达，探究肥大型肥胖ADSCs中NRF2、MFN2和ERS对细胞衰老的影响；通过将不同预处理的ADSCs移植入肥大型肥胖小鼠模型，明确NRF2/MFN2/ERS信号在肥大型肥胖小鼠胰岛素抵抗中发挥的作用。本项目将为揭示ADSCs衰老引发胰岛素抵抗的分子机制提供新认识。

The inability to recruit new adipose cells caused by the senescence of adipose stem cells is a potential cause for inappropriate expansion of adipose cells and insulin resistance of hypertrophic obesity. It is of great significance to further study its molecular pathologic mechanism. Our previous studies have shown that subcutaneous adipose- derived mesenchymal stem cells (ADSCs) of hypertrophic obese mice exhibit senescence phenotype and increased endoplasmic reticulum stress (ERS), while the activity of NRF2 and the relative expression of Mfn2 were significantly down regulated. There are potential transcription binding sites of NRF2 in Mfn2 promoter region. However, the molecular mechanism of these signal abnormalities in ADSCs senescence still needs to be further clarified. This project will verify the differences in Mfn2 transcriptional regulation by NRF2 between hypertrophic obesity and control mice through the CHIP-seq. The effects of NRF2, MFN2 and ERS on ADSCs senescence in hypertrophic obese will be investigated through in vitro gene interference and overexpression. By transplanting ADSCs with different pretreatments into hypertrophic obesity mouse models, the role of NRF2/MFN2/ERS signaling to insulin resistance of hypertrophic obese was determined. This project will provide new insights into the molecular mechanism of insulin resistance induced by ADSCs senescence.