title: Arsenic Induces Insulin Resistance in Mouse Adipocytes and Myotubes Via Oxidative Stress-Regulated Mitochondrial Sirt3-FOXO3a Signaling Pathway.
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.
authors.affiliation: *Center for Research on Environmental Disease, Department of Toxicology and Cancer Biology, University of Kentucky, 1095 Veterans Drive, Lexington, KY 40536, USA.
authors.forename: Sasidharan
authors.initials: S
authors.lastname: Padmaja Divya
authors.affiliation: *Center for Research on Environmental Disease.
authors.forename: Poyil
authors.initials: P
authors.lastname: Pratheeshkumar
authors.affiliation: *Center for Research on Environmental Disease.
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.affiliation: *Center for Research on Environmental Disease.
authors.forename: Ram
authors.initials: R
authors.lastname: Vinod Roy
authors.affiliation: *Center for Research on Environmental Disease, Department of Toxicology and Cancer Biology, University of Kentucky, 1095 Veterans Drive, Lexington, KY 40536, USA.
authors.forename: John
authors.initials: J
authors.lastname: Andrew Hitron
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, 1095 Veterans Drive, Lexington, KY 40536, USA.
authors.forename: Donghern
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, 1095 Veterans Drive, Lexington, KY 40536, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.affiliation: *Center for Research on Environmental Disease.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin, India.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Asha
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40504 and.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, 1095 Veterans Drive, Lexington, KY 40536, USA, zhuo.zhang@uky.edu.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000187:drug effects*; D056566:Sirtuin 3 / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C525046:Sirt3 protein, mouse; D014157:Transcription Factors; D013481:Superoxides; D013482:Superoxide Dismutase; D056566:Sirtuin 3; D001151:Arsenic
keywords: FOXO3a; Glut4; Sirt3; T2DM; arsenic; oxidative stress