Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor gamma in Human Skeletal Muscle Cells

Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPAR gamma induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H(2)O(2) levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulin-resistant cells, suggesting that GPx3 is required for the regulation of PPAR gamma-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPAR gamma is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.This study was supported by 21C Frontier Functional Proteomics Project from the Korean Ministry of Education, Science and Technology and MarineBio21, Ministry of Maritime Affairs and Fisheries, South Korea.Lee YS, 2008, MOL ENDOCRINOL, V22, P2176, DOI 10.1210/me.2008-0023LORENZO M, 2008, J ANIM SCI, V86, pE94Voetsch B, 2007, STROKE, V38, P41, DOI 10.1161/01.STR.0000252027.53766.2bDegenhardt T, 2006, J BIOL CHEM, V281, P39607, DOI 10.1074/jbc.M605623200Lee KS, 2006, J ALLERGY CLIN IMMUN, V118, P120, DOI 10.1016/j.jaci.2006.03.021Drevet JR, 2006, MOL CELL ENDOCRINOL, V250, P70, DOI 10.1016/j.mce.2005.12.027Houstis N, 2006, NATURE, V440, P944, DOI 10.1038/nature04634Fridlyand LE, 2006, DIABETES OBES METAB, V8, P136, DOI 10.1111/j.1463-1326.2005.00496.x*AM DIAB ASS, 2006, DIABETES CARE S1, V29, pS43Guan HP, 2005, GENE DEV, V19, P453, DOI 10.1101/gad.1263305Furukawa S, 2004, J CLIN INVEST, V114, P1752, DOI [10.1172/JCI20042162S, 10.1172/JCI200421625]Da Ros R, 2004, DIABETIC MED, V21, P1249Hildebrandt W, 2004, J MOL MED-JMM, V82, P336, DOI 10.1007/s00109-004-053-5Ferre P, 2004, DIABETES, V53, pS43Hevener AL, 2003, NAT MED, V9, P1491, DOI 10.1038/nm956Urakawa H, 2003, J CLIN ENDOCR METAB, V88, P4673, DOI 10.1210/jc.2003-030202Haber CA, 2003, AM J PHYSIOL-ENDOC M, V285, pE744, DOI 10.1152/ajpendo.00355.2002Hong HK, 2003, DIABETES RES CLIN PR, V62, P1, DOI 10.1016/S0168-8227(03)00142-6Wilson KHS, 2003, DIABETES, V52, P2151Gardner CA, 2003, EXP BIOL MED, V228, P836Kryukov GV, 2003, SCIENCE, V300, P1439Maglara AA, 2003, J PHYSIOL-LONDON, V548, P837, DOI 10.1113/jphysiol.2002.034520Girnun GD, 2002, MOL ENDOCRINOL, V16, P2793, DOI 10.1210/me.2002-0020Takebe G, 2002, J BIOL CHEM, V277, P41254, DOI 10.1074/jbc.M202773200Evans JL, 2002, ENDOCR REV, V23, P599, DOI 10.1210/er.2001.0039Brownlee M, 2001, NATURE, V414, P813Park KS, 2001, DIABETES, V50, P2837Shin CS, 2001, DIABETES CARE, V24, P733Maddux BA, 2001, DIABETES, V50, P404Inoue I, 2001, METABOLISM, V50, P3, DOI 10.1053/meta.2001.19415Antunes F, 2000, FEBS LETT, V475, P121Rosen ED, 2000, GENE DEV, V14, P1293Karasu C, 2000, EUR J PHARMACOL, V392, P163Westermann G, 2000, TRACE ELEM ELECTROLY, V17, P180Blair AS, 1999, J BIOL CHEM, V274, P36293Brigelius-Flohe R, 1999, FREE RADICAL BIO MED, V27, P951Hansen LL, 1999, J BIOL CHEM, V274, P25078Carlsson C, 1999, ENDOCRINOLOGY, V140, P3422Kenet G, 1999, ARTERIOSCL THROM VAS, V19, P2017Tirosh A, 1999, J BIOL CHEM, V274, P10595Maeda K, 1997, GENE, V190, P227Kyriakis JM, 1996, J BIOL CHEM, V271, P24313HENRY RR, 1995, DIABETES, V44, P936GIUGLIANO D, 1995, METABOLISM, V44, P363TONTONOZ P, 1994, CELL, V79, P1147MASER RL, 1994, J BIOL CHEM, V269, P27066YAMAMOTO Y, 1993, ARCH BIOCHEM BIOPHYS, V305, P541PORTER M, 1992, CLIN SCI, V83, P343CHU FF, 1992, BLOOD, V79, P3233BERRY MJ, 1991, NATURE, V353, P273YOSHIMURA S, 1991, J BIOCHEM-TOKYO, V109, P918MADDIPATI KR, 1987, J BIOL CHEM, V262, P173981