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PKC--dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase

¹Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv; ²Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel; and ³Institute of Molecular Oncology, Showa University, Tokyo Japan

Submitted 16 August 2004 ; accepted in final form 21 October 2004

Oxidative stress is thought to be one of the causative factors contributing to insulin resistance and type 2 diabetes. Previously, we showed that reactive oxygen species (ROS) production is significantly increased in adipocytes from high-fat diet-induced obese and insulin-resistant mice (HF). ROS production was also associated with the increased activity of PKC-. In the present studies, we hypothesized that PKC- contributes to ROS generation and determined their intracellular source. NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) reduced ROS levels by 50% in HF adipocytes, and inhibitors of NO synthase (L-NAME, 1 mM), xanthine oxidase (allopurinol, 100 µM), AGE formation (aminoguanidine, 10 µM), or the mitochondrial uncoupler (FCCP, 10 µM) had no effect. Rottlerin, a selective PKC- inhibitor, suppressed ROS levels by 50%. However, neither GÖ-6976 nor LY-333531, effective inhibitors toward conventional PKC or PKC-, respectively, significantly altered ROS levels in HF adipocytes. Subsequently, adenoviral-mediated expression of wild-type PKC- or its dominant negative mutant (DN-PKC-) in HF adipocytes resulted in either a twofold increase in ROS levels or their suppression by 20%, respectively. In addition, both ROS levels and PKC- activity were sharply reduced by glucose depletion. Taken together, these results suggest that PKC- is responsible for elevated intracellular ROS production in HF adipocytes, and this is mediated by high glucose and NADPH oxidase.

protein kinase C-; insulin-resistant adipcoytes

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