Wei Gang, Sun Honglin, Liu Jun-Li, Dong Kai, Liu Junli, Zhang Min
Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032 People's Republic of China.
2Henan Key Laboratory of Neurorestoratology, Henan International Joint Laboratory of Neurorestoratology for Senile Dementia, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100 Henan Province People's Republic of China.
Nutr Metab (Lond). 2020 Mar 16;17:21. doi: 10.1186/s12986-020-00440-4. eCollection 2020.
Obesity occurs when the body's energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity
In this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments.
Base on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways.
Our results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.
当身体的能量摄入持续大于能量消耗时，肥胖就会发生，而增强棕色脂肪组织（BAT）活性和（或）使白色脂肪组织（WAT）棕色化的药理学方法被认为是治疗肥胖的有前景的策略。
在本研究中，我们采取了多管齐下的方法来筛选解偶联蛋白1（UCP1）激活剂，包括计算机模拟预测、体外试验以及体内实验。
基于连通性图谱（CMAP）筛选，我们获得了多种与增强BAT活性和（或）小WAT特征具有显著相关基因表达模式的药物。特别地，我们聚焦于一种先前未报道的药物——靛玉红，一种从靛蓝植物中获得的化合物，目前主要用于治疗慢性粒细胞白血病（CML）。在当前研究中，我们的结果表明靛玉红可以增强BAT活性，体外细胞模型中表达上调和线粒体呼吸功能增强证明了这一点。此外，在小鼠模型中，靛玉红治疗抑制了高脂饮食（HFD）诱导的体重增加，改善了葡萄糖稳态并减轻了肝脂肪变性，这与能量消耗增加有关。此外，我们发现靛玉红治疗通过促进BAT中的产热和线粒体生物发生增加了BAT活性，并诱导了HFD下小鼠皮下腹股沟白色脂肪组织（sWAT）的棕色化。此外，我们的结果表明靛玉红至少部分通过激活蛋白激酶A（PKA）和p38丝裂原活化蛋白激酶（p38MAPK）信号通路诱导棕色脂肪细胞中UCP1的表达。
我们的结果清楚地表明，作为一种有效的BAT（以及米色细胞）激活剂，靛玉红可能对肥胖及其并发症的预防和治疗具有保护作用。
