Wang Xin, Yang Peng, Liu Jiangzheng, Wu Hao, Yu Weihua, Zhang Tao, Fu Han, Liu Ying, Hai Chunxu
Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
Department of Health Statistics, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
Biochimie. 2014 Nov;106:121-30. doi: 10.1016/j.biochi.2014.08.009. Epub 2014 Aug 28.
Obesity has become a worldwide public health problem, which is mainly determined by excess energy intake and adipose tissue expansion. Adipose tissue expansion can occur through hyperplasia (adipocyte differentiation) or hypertrophy. Retinoic acid was shown to inhibit adipocyte differentiation. However, the molecular mechanism is unclear. In the study, we found that all-trans-retinoic acid (ATRA) inhibited 3T3-L1 adipocyte differentiation. We did not observe significant apoptosis in differentiated adipocytes treated by ATRA. ATRA increased ROS generation and disturbed redox balance. However, antioxidant treatment did not ameliorate the reduction of lipid accumulation induced by ATRA, indicating that ROS generation was not involved in ATRA-inhibited adipocyte differentiation. ATRA reduced C/EBPα, PPARγ and its target gene expression. In the presence of ATRA, retinoic acid receptor (RAR) α/γ expression was increased. Inhibition of RARγ, but not RARα, blocked ATRA-induced reduction of PPARγ2 expression. ATRA induced a profound interaction between RARγ and C-Fos protein, reflected by Co-IP results. C-Fos was found to exhibit a differentiation-dependent DNA binding activity to PPARγ2 promoter. RARγ inhibitor significantly suppressed ATRA-inhibited DNA binding activity of C-Fos to PPARγ2 promoter, indicating that downregulation of C-Fos activity mediated activation of RARγ-exerted reduction of PPARγ2 expression and thus inhibition of adipocyte differentiation induced by ATRA. Taken together, these data demonstrates that RARγ-C-Fos-PPARγ2 signaling rather than ROS generation is critical for ATRA-inhibited adipocyte differentiation.
肥胖已成为一个全球性的公共卫生问题，这主要由能量摄入过多和脂肪组织扩张所决定。脂肪组织扩张可通过增生（脂肪细胞分化）或肥大发生。维甲酸被证明可抑制脂肪细胞分化。然而，其分子机制尚不清楚。在本研究中，我们发现全反式维甲酸（ATRA）抑制3T3-L1脂肪细胞分化。我们未观察到经ATRA处理的分化脂肪细胞中有明显凋亡。ATRA增加活性氧（ROS）生成并扰乱氧化还原平衡。然而，抗氧化剂处理并未改善ATRA诱导的脂质积累减少，这表明ROS生成不参与ATRA抑制的脂肪细胞分化。ATRA降低了C/EBPα、PPARγ及其靶基因的表达。在ATRA存在的情况下，维甲酸受体（RAR）α/γ的表达增加。抑制RARγ而非RARα可阻断ATRA诱导的PPARγ2表达降低。ATRA诱导RARγ与C-Fos蛋白之间发生深刻相互作用，这通过免疫共沉淀（Co-IP）结果得以体现。发现C-Fos对PPARγ2启动子表现出依赖分化的DNA结合活性。RARγ抑制剂显著抑制了ATRA抑制的C-Fos对PPARγ2启动子的DNA结合活性，表明C-Fos活性下调介导了RARγ激活所导致的PPARγ2表达降低，进而抑制了ATRA诱导的脂肪细胞分化。综上所述，这些数据表明RARγ-C-Fos-PPARγ2信号通路而非ROS生成对于ATRA抑制的脂肪细胞分化至关重要。
