Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages.

Wang, Yawei; Tang, Binlin; Long, Lei; Luo, Peng; Xiang, Wei; Li, Xueru; Wang, Huilan; Jiang, Qingzhi; Tan, Xu; Luo, Shenglin; Li, Huijuan; Wang, Ziwen; Chen, Zelin; Leng, Yu; Jiang, Zhongyong; Wang, Yang; Ma, Le; Wang, Rui; Zeng, Chunyu; Liu, Zujuan; Wang, Yu; Miao, Hongming; Shi, Chunmeng

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.