Stem cells 2013 July-7


Differentiation of Human Adipose-Derived Stem Cells into Fat Involves Reactive Oxygen Species and Forkhead Box O1 Mediated Upregulation of Antioxidant Enzymes

Stem Cells Dev. 2013 Mar 15;22(6):878-88.

Masayoshi Higuchi, Gregory J. Dusting, Hitesh Peshavariya, Fan Jiang, Sarah Tzu-Feng Hsiao, Elsa C. Chan, and Guei-Sheung Liu


Adipogenesis is a process by which new adipocytes formed from mesenchymal stem cells or other precursor cells. Expansion of the white adipose tissue results in development of obesity, which has significant contributions to hyperglycemia, hyperlipidemia, insulin resistance, chronic inflammation, type 2 diabetes and atherosclerosis. Both reactive oxygen species (ROS) and the transcription factor forkhead box protein (FOXOs) family are involved in regulating adipogenic differentiation of pre-adipocytes and stem cells to produce fat. While FOXOs have a pivotal role in maintaining cellular redox homeostasis, the interactions between ROS and FOXOs during adipogenesis have not been evaluated. Here we examined how ROS and FOXOs regulate adipogenesis in human adipose-derived stem cells (hASC).


Human adipose-derived stem cells were isolated from abdominal fat and characterized by mesenchymal stem cell markers (CD29, CD44, CD73, CD90 and CD105, but not CD45 or CD31). The standard adipogenic cocktail medium (IDII; insulin, dexamethasone, indomethacin and IBMX) was used to induce adipogenic differentiation of hASC to adipocytes in vitro.


Using IDII cocktail, adipogenesis was induced in hASC, which was accompanied by enhanced H2O2 generation and upregulation of FOXO1 and FOXO3. Treatment with the antioxidant N-acetylcysteine (NAC) or silencing FOXO1 expression partially inhibited IDII-induced adipogenesis. Antioxidant enzymes including SOD2, catalase and GPx were upregulated by IDII during adipogenesis, and these effects were blunted by FOXO1 silencing.


Our data therefore suggests that ROS and FOXO1 have independent effects in promoting adipogenic differentiation of hASC. FOXO1 may act as a self-regulatory mechanism which protects cells from excessive oxidative stress by maintaining a balance of ROS generation and antioxidant enzyme expression in hASC undergoing adipogenesis, to avoid oxidative stress and cell damage. Approaches targeting ROS and/or FOXO1 may bring new strategies for prevention or treatment of obesity.

Guei-Sheung Liu


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