Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages.
Nature Communications; 1/4/2021, Vol. 12 Issue 1, p1-16, 16p
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. Adipose tissue macrophages are central to controlling inflammation in the context of obesity. Here the authors present a new infrared dye (IR-61) that accumulates in the mitochondria of these cells resulting in anti-inflammatory effects that counter obesity-associated pathology in mice. [ABSTRACT FROM AUTHOR]
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