Arsenic Induces Insulin Resistance in Mouse 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

doi:10.1093/toxsci/kfv089

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Arsenic Induces Insulin Resistance in Mouse Adipocytes and Myotubes Via Oxidative Stress-Regulated Mitochondrial Sirt3-FOXO3a Signaling Pathway

Journal article

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Arsenic Induces Insulin Resistance in Mouse 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, …

Toxicological sciences, Vol.146(2), pp.290-300

08/2015

DOI: 10.1093/toxsci/kfv089

PMID: 25979314

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Abstract

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 (Δψm) 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)-1α, a broad and powerful regulator of reactive oxygen species (ROS) metabolism. Forced expression of Sirt3 or MnSOD in mouse myotubes elevated Δψm and 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.

Adipocytes - drug effects

Adipocytes - metabolism

Animals

Arsenic - toxicity

Forkhead Box Protein O3

Forkhead Transcription Factors - metabolism

Insulin Resistance

Mice

Mitochondria - metabolism

Muscle Fibers, Skeletal - drug effects

Muscle Fibers, Skeletal - metabolism

Oxidative Stress - drug effects

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

Signal Transduction - drug effects

Sirtuin 3 - metabolism

Superoxide Dismutase - metabolism

Superoxides - metabolism

Transcription Factors

Details

Title: Subtitle: Arsenic Induces Insulin Resistance in Mouse Adipocytes and Myotubes Via Oxidative Stress-Regulated Mitochondrial Sirt3-FOXO3a Signaling Pathway
Creators: Sasidharan Padmaja Divya - University of Kentucky
Poyil Pratheeshkumar - *Center for Research on Environmental Disease,
Young-Ok Son - Center for Research on Environmental Disease
Ram Vinod Roy - Center for Research on Environmental Disease
John Andrew Hitron - University of Kentucky
Donghern Kim - University of Kentucky
Jin Dai - University of Kentucky
Lei Wang - *Center for Research on Environmental Disease,
Padmaja Asha - Cochin University of Science and Technology
Bin Huang - University of Kentucky
Mei Xu - University of Kentucky
Jia Luo - University of Kentucky
Zhuo Zhang - University of Kentucky
Resource Type: Journal article
Publication Details: Toxicological sciences, Vol.146(2), pp.290-300
DOI: 10.1093/toxsci/kfv089
PMID: 25979314
NLM abbreviation: Toxicol Sci
ISSN: 1096-6080
eISSN: 1096-0929
Language: English
Date published: 08/2015
Academic Unit: Pathology
Record Identifier: 9984201248402771

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