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

• Published in: Nature communications Vol. 12; no. 1; p. 102
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 04.01.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adipose tissue; Adipose Tissue - metabolism; AKT protein; Animals; Anti-inflammatory agents; Body Weight - drug effects; Cell activation; Disorders; Drug Delivery Systems; Fatty liver; Fatty Liver - genetics; Fatty Liver - pathology; Inflammation; Inflammation - genetics; Inflammation - pathology; Infrared radiation; Insulin; Insulin Resistance; Liver - metabolism; Liver - pathology; Macrophage Activation - drug effects; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Medical treatment; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Obesity; Obesity - drug therapy; Obesity - genetics; Obesity - pathology; Oxidative phosphorylation; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; RAW 264.7 Cells; Reactive Oxygen Species - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Therapeutic targets; Weight Loss - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20315-9

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.