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

Yawei Wang, Binlin Tang, Lei Long, Peng Luo, Wei Xiang, Xueru Li, Huilan Wang, Qingzhi Jiang, Xu Tan, Shenglin Luo, Huijuan Li, Ziwen Wang, Zelin Chen, Yu Leng, Zhongyong Jiang, Yang Wang, Le Ma, Rui Wang, Chunyu Zeng, Zujuan Liu, Yu Wang (), Hongming Miao () and Chunmeng Shi ()
Additional contact information
Yawei Wang: Burns and Combined Injury, Third Military Medical University
Binlin Tang: Burns and Combined Injury, Third Military Medical University
Lei Long: Burns and Combined Injury, Third Military Medical University
Peng Luo: Burns and Combined Injury, Third Military Medical University
Wei Xiang: Third Military Medical University
Xueru Li: Burns and Combined Injury, Third Military Medical University
Huilan Wang: Burns and Combined Injury, Third Military Medical University
Qingzhi Jiang: Burns and Combined Injury, Third Military Medical University
Xu Tan: Burns and Combined Injury, Third Military Medical University
Shenglin Luo: Burns and Combined Injury, Third Military Medical University
Huijuan Li: Burns and Combined Injury, Third Military Medical University
Ziwen Wang: Burns and Combined Injury, Third Military Medical University
Zelin Chen: Burns and Combined Injury, Third Military Medical University
Yu Leng: Burns and Combined Injury, Third Military Medical University
Zhongyong Jiang: Burns and Combined Injury, Third Military Medical University
Yang Wang: Burns and Combined Injury, Third Military Medical University
Le Ma: Burns and Combined Injury, Third Military Medical University
Rui Wang: Daping Hospital, Third Military Medical University
Chunyu Zeng: Daping Hospital, Third Military Medical University
Zujuan Liu: Burns and Combined Injury, Third Military Medical University
Yu Wang: Burns and Combined Injury, Third Military Medical University
Hongming Miao: Third Military Medical University
Chunmeng Shi: Burns and Combined Injury, Third Military Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20315-9

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