hPER3 通过 hHSP90AA1 介导的 Notch1 通路抑制促进脂肪生成。
hPER3 promotes adipogenesis via hHSP90AA1-mediated inhibition of Notch1 pathway.
机构信息
Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
Department of Bariatric and Metabolic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
出版信息
Cell Death Dis. 2021 Mar 19;12(4):301. doi: 10.1038/s41419-021-03584-0.
The period circadian regulator 3 (PER3) has been reported to play a negative role in human immortalized bone marrow-derived Scp-1 cells (iBMSCs) and patient adipose-derived stromal cells (PASCs) or a negative/positive role in mice adipogenesis. However, human PER3 (hPER3) was identified as a positive regulator of human adipose tissue-derived stromal cells (hADSCs) adipogenesis in this study. Silencing or overexpression of hPER3 in hADSCs inhibited and promoted adipogenesis in vitro. In vivo, the overexpression of hPER3 increased high-fat diet-induced inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) forms, increasing systemic glucose intolerance and insulin resistance. Molecularly, hPER3 does not interact with hPPARγ, but represses Notch1 signaling pathway to enhance adipogenesis by interacting with hHSP90AA1, which is able to combine with the promoter of hNotch1 and inactivate its expression. Thus, our study revealed hPER3 as a critical positive regulator of hADSCs adipogenesis, which was different from the other types of cells, providing a critical role of it in treating obesity.
周期节律调节器 3（PER3）已被报道在人类永生化骨髓来源的 Scp-1 细胞（iBMSCs）和患者脂肪来源的基质细胞（PASCs）中发挥负调控作用，或者在小鼠脂肪生成中发挥负/正调控作用。然而，在本研究中，人类 PER3（hPER3）被鉴定为人类脂肪组织来源的基质细胞（hADSCs）脂肪生成的正调控因子。在 hADSCs 中沉默或过表达 hPER3 可抑制和促进体外脂肪生成。在体内，hPER3 的过表达增加了高脂肪饮食诱导的腹股沟白色脂肪组织（iWAT）和附睾白色脂肪组织（eWAT）的形成，增加了全身葡萄糖不耐受和胰岛素抵抗。从分子水平上看，hPER3 不与 hPPARγ 相互作用，而是通过与 hHSP90AA1 相互作用来抑制 Notch1 信号通路，从而增强脂肪生成，hHSP90AA1 能够与 hNotch1 的启动子结合并使其失活。因此，我们的研究揭示了 hPER3 作为 hADSCs 脂肪生成的关键正调控因子，这与其他类型的细胞不同，为其在肥胖治疗中的作用提供了重要依据。
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