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Molecular and Cellular Biology, January 2009, p. 20-30, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.00544-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor {gamma} in Human Skeletal Muscle Cells{triangledown} ,{dagger}

Sung Soo Chung,1,§ Min Kim,1,§ Byoung-Soo Youn,2 Nam Seok Lee,2 Ji Woo Park,2 In Kyu Lee,3 Yun Sok Lee,4 Jae Bum Kim,4 Young Min Cho,1 Hong Kyu Lee,1 and Kyong Soo Park1*

Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, South Korea,1 AdipoGen Inc., College of Life Science and Biotechnology, Korea University, Rm 641-B, 1, 5-ka, Anam-dong, Sungbuk-ku, Seoul, South Korea,2 Department of Internal Medicine, Kyungpook National University, Daegu, South Korea,3 Research Center for Functional Cellulomics, Department of Biological Sciences, Seoul National University, Seoul 151-742, South Korea4

Received 4 April 2008/ Returned for modification 7 May 2008/ Accepted 10 October 2008

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 H2O2 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.

* Corresponding author. Mailing address: Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea. Phone: 82-2-2072-2946. Fax: 82-2-3676-8309. E-mail: kspark{at}snu.ac.kr

{triangledown} Published ahead of print on 20 October 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

§ These two authors contributed equally to this work.

Molecular and Cellular Biology, January 2009, p. 20-30, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.00544-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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