Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, China.; Key Laboratory of Birth Defects and Related Diseases of Women and children (Sichuan University), Ministry of Education, Chengdu 610041, Sichuan, China.
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, China.; Key Laboratory of Birth Defects and Related Diseases of Women and children (Sichuan University), Ministry of Education, Chengdu 610041, Sichuan, China..
Int Immunopharmacol. 2023 Aug;121:110467. doi: 10.1016/j.intimp.2023.110467. Epub 2023 Jun 20.
Recently, emerging evidence has shown that LncRNA MEG3 is involved in adipocyte inflammation and insulin resistance progression, however, the specific mechanism of action remains unclear. In this study, we found that LncRNA MEG3 expression was increased in TNF-α stimulated 3T3-L1 mature adipocytes, and inflammatory factors IL-6 and MCP-1 secretion levels were increased, cell apoptosis and caspase3 activity was enhanced, ROS content was increased, and iNOS protein expression was increased. Moreover, TNF-α treatment attenuated glucose uptake, promoted triglyceride accumulation, inhibited GLUT4 protein expression at the plasma membrane, and reduced the phosphorylation levels of AMPK and ACC in the cells. Interestingly, we found that transfection of si-MEG3 reversed TNF-α caused inflammatory injury and insulin resistance of 3T3-L1 mature adipocytes. Next, we found that IGF2BP2 is an RNA binding protein of LncRNA MGE3 and transfection of si-IGF2BP2 reversed TNF-α caused inflammatory injury and insulin resistance in 3T3-L1 mature adipocytes, the same effects as transfection of si-MEG3. Mechanistically, LncRNA MGE3 was able to aggravate adipocyte inflammatory injury and dysregulation of insulin sensitivity by activating TLR4 pathway through upregulating the protein expression of IGF2BP2. In vivo findings showed that HFD mice with knockdown of MEG3 had reduced body weight, lower glucose concentrations and insulin levels in plasma, decreased inflammatory factors secretion, and reduced MEG3 and IGF2BP2 expression in epididymal adipose tissues and reduced fat accumulation in mice compared with HFD mice. Our results indicate that LncRNA MEG3 can aggravate chronic inflammation and insulin resistance in adipocytes by activating TLR4/NF-κB signaling pathway via targeting IGF2BP2.
最近的研究表明，LncRNA MEG3 参与脂肪细胞炎症和胰岛素抵抗的进展，但具体的作用机制尚不清楚。在本研究中，我们发现 TNF-α 刺激的 3T3-L1 成熟脂肪细胞中 LncRNA MEG3 的表达增加，炎症因子 IL-6 和 MCP-1 的分泌水平增加，细胞凋亡和 caspase3 活性增强，ROS 含量增加，iNOS 蛋白表达增加。此外，TNF-α 处理减弱了葡萄糖摄取，促进了甘油三酯的积累，抑制了质膜上 GLUT4 蛋白的表达，并降低了细胞中 AMPK 和 ACC 的磷酸化水平。有趣的是，我们发现转染 si-MEG3 逆转了 TNF-α 引起的 3T3-L1 成熟脂肪细胞的炎症损伤和胰岛素抵抗。接下来，我们发现 IGF2BP2 是 LncRNA MGE3 的 RNA 结合蛋白，转染 si-IGF2BP2 逆转了 TNF-α 引起的 3T3-L1 成熟脂肪细胞的炎症损伤和胰岛素抵抗，与转染 si-MEG3 的效果相同。机制上，LncRNA MGE3 通过上调 IGF2BP2 的蛋白表达，能够通过激活 TLR4 通路加重脂肪细胞的炎症损伤和胰岛素敏感性失调。体内研究结果表明，与 HFD 小鼠相比，敲低 MEG3 的 HFD 小鼠体重减轻，血浆中葡萄糖浓度和胰岛素水平降低，炎症因子分泌减少，附睾脂肪组织中 MEG3 和 IGF2BP2 的表达降低，脂肪堆积减少。我们的研究结果表明，LncRNA MEG3 通过靶向 IGF2BP2 激活 TLR4/NF-κB 信号通路，可加重脂肪细胞的慢性炎症和胰岛素抵抗。
