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

Nat Commun. 2021 Jan 4;12(1):102. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Animals
  • Body Weight / drug effects
  • Drug Delivery Systems*
  • Fatty Liver / genetics
  • Fatty Liver / pathology
  • Inflammation / genetics
  • Inflammation / pathology
  • Insulin Resistance
  • Liver / metabolism
  • Liver / pathology
  • Macrophage Activation / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Obesity / drug therapy*
  • Obesity / genetics
  • Obesity / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • RAW 264.7 Cells
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*
  • Weight Loss / drug effects


  • RNA, Messenger
  • Reactive Oxygen Species
  • Small Molecule Libraries
  • Proto-Oncogene Proteins c-akt