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This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 296/6/E1326    most recent 90921.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kobayashi, H. Articles by Shimomura, I. PubMed PubMed Citation Articles by Kobayashi, H. Articles by Shimomura, I.

Dysregulated glutathione metabolism links to impaired insulin action in adipocytes

¹Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka; and ²Institute of Clinical Research and ³Department of Internal Medicine, National Hospital Organization, Kure Medical Center, Hiroshima, Japan

Submitted 15 November 2008 ; accepted in final form 13 April 2009

Oxidative stress plays an important role in obesity-related metabolic diseases. Glutathione peroxidase (GPX) is an antioxidant enzyme downregulated in adipose tissue of obese mice. However, the role of GPX in adipocytes remains elusive. The objective of this study was to clarify the pathophysiological changes in GPX activity and glutathione metabolism and their roles in the pathogenesis of insulin resistance in adipocytes. To achieve this goal, we measured cellular GPX activity, glutathione (GSH) contents, GSH/GSSG ratio, and mRNA expression of -glutamylcysteine synthetase (-GCS), a rate-limiting enzyme for de novo GSH synthesis, in adipose tissue of control and ob/ob mice and in 3T3-L1 adipocytes treated with insulin, H₂O₂, free fatty acid (FFA), or TNF. Furthermore, we investigated the effects of GPX inhibition with a specific GPX inhibitor or RNA interference against GPX, H₂O₂, and reduced GSH on insulin signaling in 3T3-L1 adipocytes. ob/ob Mice showed not only a decrease in cellular activity of GPXs (GPX1, -4, and -7) but also an increase in -GCS expression, resulting in increased GSH contents in adipose tissue. These alterations in glutathione metabolism were also observed during differentiation of 3T3-L1 cells and their exposure to insulin, FFA, or H₂O₂. Inhibition of GPX activity, addition of GSH, and H₂O₂ resulted in impaired insulin signaling in 3T3-L1 adipocytes. These results suggest that decreased GPX activity and increased -GCS expression lead to overaccumulation of GSH, which might be involved in the pathogenesis of insulin resistance in obesity.

glutathione peroxidase; -glutamylcysteine synthetase; oxidative stress; insulin resistance