Adipocytes and myotubes via oxidative stress-regulated mitochondrial sirt3-FOXO3a signaling pathway

Sasidharan Padmaja Divya, Poyil Pratheeshkumar, Young Ok Son, Ram Vinod Roy, John Andrew Hitron, Donghern Kim, Jin Dai, Lei Wang, Padmaja Asha, Bin Huang, Mei Xu, Jia Luo, Zhuo Zhang

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


Chronic exposure to arsenic via drinking water is associated with an increased risk for development of type 2 diabetes mellitus (T2DM). This study investigates the role of mitochondrial oxidative stress protein Sirtuin 3 (Sirt3) and its targeting proteins in chronic arsenic-induced T2DM in mouse adipocytes and myotubes. The results show that chronic arsenic exposure significantly decreased insulin-stimulated glucose uptake (ISGU) in correlation with reduced expression of insulin-regulated glucose transporter type 4 (Glut4). Expression of Sirt3, a mitochondrial deacetylase, was dramatically decreased along with its associated transcription factor, forkhead box O3 (FOXO3a) upon arsenic exposure. A decrease in mitochondrial membrane potential (Dwm) was observed in both 3T3L1 adipocytes and C2C12 myotubes treated by arsenic. Reduced FOXO3a activity by arsenic exhibited a decreased binding affinity to the promoters of both manganese superoxide dismutase (MnSOD) and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1a, a broad and powerful regulator of reactive oxygen species (ROS) metabolism. Forced expression of Sirt3 or MnSOD in mouse myotubes elevated Dwmand restored ISGU inhibited by arsenic exposure. Our results suggest that Sirt3/FOXO3a/MnSOD signaling plays a significant role in the inhibition of ISGU induced by chronic arsenic exposure.

Original languageEnglish
Pages (from-to)290-300
Number of pages11
JournalToxicological Sciences
Issue number2
StatePublished - Aug 1 2015

Bibliographical note

Publisher Copyright:
© The Author 2015.


  • Arsenic
  • FOXO3a
  • Glut4
  • Oxidative stress
  • Sirt3
  • T2DM

ASJC Scopus subject areas

  • Toxicology


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