Hypoxia induces adipocyte differentiation of adipose-derived stem cells by triggering reactive oxygen species generation

Cell Biol Int. 2014 Jan;38(1):32-40. doi: 10.1002/cbin.10170. Epub 2013 Sep 12.


Generation of reactive oxygen species (ROS) by NADPH oxidase 4 (Nox4) induces the proliferation and migration of adipose-derived stem cells (ASCs). However, the functional role of mitochondrial ROS (mtROS) generation in ASCs is unknown. Therefore, we have investigated whether hypoxia induces the differentiation of ASCs via ROS generation. We also have tried to identify the cellular mechanisms of ROS generation underlying adipocyte differentiation. Hypoxia (2%) and ROS generators, such as antimycin and rotenone, induced adipocyte differentiation, which was attenuated by an ROS scavenger. Although Nox4 generates ROS and regulates proliferation of ASCs, Nox4 inhibition or Nox4 silencing did not inhibit adipocyte differentiation; indeed fluorescence intensity of mito-SOX increased in hypoxia, and treatment with mito-CP, a mtROS scavenger, significantly reduced hypoxia-induced adipocyte differentiation. Phosphorylation of Akt and mTOR was induced by hypoxia, while inhibition of these molecules prevented adipocyte differentiation. Thus hypoxia induces adipocyte differentiation by mtROS generation, and the PI3K/Akt/mTOR pathway is involved.

Keywords: adipocyte differentiation; adipose-derived stem cells; hypoxia; mitochondria; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology
  • Antimycin A / analogs & derivatives
  • Antimycin A / pharmacology
  • Cell Differentiation* / drug effects
  • Cell Hypoxia*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclic N-Oxides / chemistry
  • Cyclic N-Oxides / pharmacology
  • Free Radical Scavengers / pharmacology
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • NADPH Oxidase 4
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism*
  • Rotenone / pharmacology
  • Signal Transduction
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • TOR Serine-Threonine Kinases / metabolism


  • Cyclic N-Oxides
  • Free Radical Scavengers
  • Organophosphorus Compounds
  • Reactive Oxygen Species
  • mito-carboxy proxyl
  • Rotenone
  • antimycin
  • Antimycin A
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX4 protein, human
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt