Glutathione Depletion Prevents Diet‐Induced Obesity and Enhances Insulin Sensitivity

Abstract

nature publishing group short communications integrative PhysiologyChronic oxidative stress has been implicated in the development of type 2 diabetes and its associated cardiovascular complications (1,2). Reactive oxygen species (ROS) accumulate in obesity and considerable experimental and clinical data have linked oxidative stress to insulin resistance and β-cell dysfunction (1,3). At the cellular level, chronic oxidative stress resulting from prolonged exposure to high concentrations of ROS alters insulin-stimulated glucose update, an effect that is thought to be mediated by impaired insulin signaling (2,3). However, considering that certain ROS may also serve as important second messengers and signaling intermediates (4), the causal contribution of physiological concentrations of ROS to insulin resistance and obesity remains controversial. For example, transient and low dose concentrations of H 2 O 2 enhance insulin sensitivity (5,6), indicating that the role of ROS in glucose metabolism may depend on the ROS concentration and the mechanisms of their generation. Since glutathione peroxidase (GPx) constitutes the principal antioxidant defense system to scavenge physiological concentrations of H 2 O 2 in mammals (6), we investigated in this study the role of pharmacological glutathione depletion on diet-induced obesity and insulin sensitivity. Surprisingly, depletion of endogenous glutathione protected mice from obesity, preserved insulin sensitivity, and increased energy expenditure, pointing to a more complex role of endogenous ROS in diabetes and energy balance than previously anticipated. Methods and Proceduresanimal experiments C57BL/6 mice were obtained from The Jackson Laboratory. All mice were housed in plexiglas-ventilated cages within a pathogen-free barrier facility that maintained a 12-hour light/12-hour dark cycle. Mice had access to autoclaved water and pellet food ad libitum. Prior to 11 weeks of age, all mice were fed a standard rodent chow diet containing ~5% kcal fat (Harlan Teklad). At 11 weeks of age, all mice were fed a high-fat diet (HFD) containing 45% kcal from fat (Research Diets, New Brunswick, NJ). During this period L-buthionine-(S,R)-sulfoximine (BSO, Sigma-Aldrich, St Louis, MO) was administered in the drinking water of the treatment group at a concentration of 30 mmol/l. BSO was dissolved in diH 2 O and filtered before use. Weight gain was monitored weekly. Body compositionBody composition was analyzed after 6 weeks of HFD feeding using quantitative magnetic resonance imaging (EchoMRI, Echo Medical Systems, Houston, TX) as described (7). Metabolic measurementsGlucose tolerance tests were performed in HFD-fed animals after an overnight fasting period (n = 10 and n = 9 for HFD + BSO, respectively). Following an intraperitoneal injection of glucose dissolved in water (2 g/kg body weight), blood glucose levels were analyzed before and 15, 30, 60, 90, and 120 min after injection using a Freestyle Flash Glucometer (Abbott Laboratories, Chicago, IL). Insulin sensitivity was analyzed in f...

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