Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk, 38543, Republic of Korea.
Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk, 38543, Republic of Korea.
Biochimie. 2018 Mar;146:97-104. doi: 10.1016/j.biochi.2017.11.021. Epub 2017 Dec 5.
Browning of white adipocytes (beiging) is an attractive therapeutic strategy against obesity and its associated metabolic complications. Nobiletin (NOB) is a polymethoxylated flavone present in citrus fruits and has been reported to have anti-obesity effects. Here, we report that nobiletin exerts dual modulatory effects on adipocytes via induction of browning in 3T3-L1 white adipocytes and amelioration of stress in adipocytes. Nobiletin-induced beiging was investigated by determining expression levels of beige-specific genes and proteins by RT-PCR and immunoblot analysis, respectively. Nobiletin treatment rapidly elevated the expression levels of beige-specific genes such as Cd137, Cidea, Tbx1, and Tmem26. Further, nobiletin enhanced expression of the key transcription factors C/EBPβ, PPARδ, and PPARα, which are responsible for remodeling of white adipocytes. Nobiletin also strikingly activated HIB1B brown adipocytes and induced mitochondrial biogenesis in 3T3-L1 white adipocytes. In addition, nobiletin altered the expression of several lipid metabolism-related proteins such as ACOX1, CPT1, FAS, p-PLIN, SREBP and SIRT1. Moreover, nobiletin ameliorated stress in adipocytes by inhibiting expression levels of key stress molecules such as JNK and c-JUN. Nobiletin-induced browning could be mediated by tight regulation of kinases, as nobiletin induced PKA and p-AMPK at the protein expression level, and inhibition of PKA and p-AMPK by H-89 and dorsomorphin, respectively, abolished expression of the thermogenic markers PGC-1α and UCP1. Taken together, our findings suggest that nobiletin plays a modulatory role in adipocytes via induction of browning in 3T3-L1 white adipocytes and activation of HIB1B brown adipocytes combined with amelioration of stress in adipocytes, thereby exhibiting therapeutic potential against obesity.
白色脂肪细胞的棕色化（米色化）是一种有吸引力的治疗肥胖及其相关代谢并发症的策略。川陈皮素（NOB）是一种存在于柑橘类水果中的多甲氧基黄酮，据报道具有抗肥胖作用。在这里，我们报告川陈皮素通过诱导 3T3-L1 白色脂肪细胞的棕色化和改善脂肪细胞的应激来对脂肪细胞发挥双重调节作用。通过 RT-PCR 和免疫印迹分析分别测定米色特异性基因和蛋白质的表达水平来研究川陈皮素诱导的米色化。川陈皮素处理可迅速升高米色特异性基因如 Cd137、Cidea、Tbx1 和 Tmem26 的表达水平。此外，川陈皮素增强了负责重塑白色脂肪细胞的关键转录因子 C/EBPβ、PPARδ 和 PPARα 的表达。川陈皮素还显著激活了 HIB1B 棕色脂肪细胞，并诱导了 3T3-L1 白色脂肪细胞中的线粒体生物发生。此外，川陈皮素改变了几种与脂质代谢相关的蛋白质如 ACOX1、CPT1、FAS、p-PLIN、SREBP 和 SIRT1 的表达。此外，川陈皮素通过抑制关键应激分子如 JNK 和 c-JUN 的表达水平来改善脂肪细胞的应激。川陈皮素诱导的米色化可能是通过对激酶的紧密调节来介导的，因为川陈皮素在蛋白质表达水平上诱导了 PKA 和 p-AMPK，而 H-89 和 dorsomorphin 分别抑制了 PKA 和 p-AMPK，从而消除了热原标记物 PGC-1α 和 UCP1 的表达。总之，我们的研究结果表明，川陈皮素通过诱导 3T3-L1 白色脂肪细胞的米色化和激活 HIB1B 棕色脂肪细胞以及改善脂肪细胞的应激，在脂肪细胞中发挥调节作用，从而表现出治疗肥胖的潜力。
