Editors' ChoiceRedox Signaling

The Sensitive Side of ROS

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Science Signaling  13 Oct 2009:
Vol. 2, Issue 92, pp. ec334
DOI: 10.1126/scisignal.292ec334

High concentrations of reactive oxygen species (ROS) can induce cellular damage and can be neutralized by antioxidant enzymes such as glutathione peroxidase 1 (Gpx1). However, low concentrations of ROS can participate in cellular signaling events. In addition to triggering the activation of the phosphatidylinosinol 3-kinase (PI3K) pathway and downstream effectors such as Akt, insulin also causes generation of the ROS H2O2, which reversibly oxidizes PTEN, the phosphatase that opposes PI3K signaling. Loh et al. investigated the role of low concentrations of ROS in insulin signaling. When treated with insulin, mouse embryonic fibroblasts from Gpx1–/– mice showed increased production of H2O2, Akt activation (as assessed by phosphorylation at Ser473), and oxidation of PTEN compared with those from wild-type mice; some of these effects were negated by the Gpx1 mimetic ebselen or the NADP(H) oxidase inhibitor DPI (diphenylene iodonium chloride). Compared with wild-type mice, Gpx1–/– mice showed greater insulin sensitivity on a high-fat diet (HFD), which was attributed to increased glucose uptake by muscle, but not other tissues such as white adipose tissue. Muscle from Gpx1–/– mice demonstrated Akt activation (as shown by increased phosphorylation of Akt and the Akt substrate AS160), and myotubes from Gpx1–/– mice showed increased H2O2 production, Akt activation, and PTEN oxidation, compared with those from wild-type mice. Administering the antioxidant N-acetylcysteine to Gpx1–/– mice before HFD reduced H2O2 production in muscle (but not in liver or plasma), Akt activation, and insulin sensitivity to that seen in wild-type mice. Insulin sensitivity and Akt signaling were enhanced in muscle from exercised Gpx1–/– mice compared with that from wild-type mice, but only after the mice were exercised in two periods, a finding that was attributed to a Gpx1-mediated decline in exercise-induced ROS in muscle of resting wild-type mice (an effect that would be expected to be absent in Gpx1–/– mice). Thus, low concentrations of ROS promote insulin sensitivity in muscle, and the authors propose that this effect is mediated by oxidation of PTEN by ROS produced by insulin, thereby promoting PI3K signaling.

K. Loh, H. Deng, A. Fukushima, X. Cai, B. Boivin, S. Galic, C. Bruce, B. J. Shields, B. Skiba, L. M. Ooms, N. Stepto, B. Wu, C. A. Mitchell, N. K. Tonks, M. J. Watt, M. A. Febbraio, P. J. Crack, S. Andrikopoulos, T. Tiganis, Reactive oxygen species enhance insulin sensitivity. Cell Metab. 10, 260–272 (2009). [PubMed]