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TO THE EDITOR: The article by Findeisen et al. titled “Glutathione Depletion Prevents Diet-Induced Obesity and Enhances Insulin Sensitivity' (published online on 29 September 2011) suggests that depletion of glutathione is associated with potential benefits on obesity and insulin resistance. However, the article has some major omissions that require clarification, without which the conclusions reached by the authors are invalid.

First, the central premise of this study is that glutathione depletion has potential benefits. The authors conclusively state that “we demonstrate pharmacologic depletion of the antioxidant glutathione”, but in the manuscript, I could not find any reported concentrations of reduced or oxidized glutathione, ratios of GSH (reduced glutathione):GSSG (oxidized glutathione). This study also discusses the role of reactive oxygen species (ROS) on glucose metabolism, and again no measures of ROS are reported. That there is glutathione depletion or ROS elevation appears to be an assumption by the authors (based on previous evidence from other studies that use buthionine sulfoximine (BSO) to deplete GSH), but there is no evidence that this actually occurred in this study. If these data are not reported, all conclusions about the role of glutathione or ROS on obesity or insulin sensitivity from the Findeisen study are invalid.

Next, the authors report that after animals consumed a high-fat diet ad libitum for 3 weeks, food and water intake were measured using a calorimetry system over 72 h, with the first 24 h devoted to adaptation. Were these measurements done on a single occasion, or multiple times during the course of the study? Did the authors confirm that there were no differences in feeding and drinking between the two groups over the 6-week duration of the study? In our lab, we have seen a wide variation in feeding patterns in mice, and the need for frequent monitoring of feed intake is critical. Indeed the mice could well have had a differential response to feeding behavior in their own cages, which could have contributed to a lack of weight gain as seen in this study. Pair-feeding, or daily feed monitoring is necessary to document that both groups consumed equivalent amounts of feed daily.

Finally, could the relatively higher dose of 30 mmol/l of BSO used in this study have led to toxicity and therefore decreased weight gain? Evidence from a study “A Novel Model of Continuous Depletion of Glutathione in Mice Treated With L-buthionine (S,R)-sulfoximine” by Watanabe et al. (1), showed that using BSO at a dose of 30 mmol/l over 14 days in mice was associated with a significant decrease in liver weight and 41.2% increase in aspartate aminotransferase concentrations, although they did not find an increase in other liver functions. However the fact that these effects were seen after only 14 days of exposure to 30 mmol/l dose of BSO has implications for the study by Findeisen et al., where an identical dose of 30 mmol/l of BSO was used for a much longer duration of 42 days. Were organ weights, or liver and renal functions measured to exclude toxicity in mice receiving BSO?

Acknowledgment

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This work was supported by the NIH funded Diabetes and Endocrinology Research Center (NIH P30DK079638), at Baylor College of Medicine. This was also supported by a pilot project grant from the Huffington Center on Aging at Baylor College of Medicine.

Disclosure

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  4. REFERENCE

The author declared no conflict of interest.

REFERENCE

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  2. Acknowledgment
  3. Disclosure
  4. REFERENCE
  • 1
    Watanabe T, Sagisaka H, Arakawa S et al. A novel model of continuous depletion of glutathione in mice treated with L-buthionine (S,R)-sulfoximine. J Toxicol Sci 2003;28: 455469.