Journal of Biological Chemistry
Volume 294, Issue 7, 15 February 2019, Pages 2340-2352
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Metabolism
Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes

https://doi.org/10.1074/jbc.RA118.004253Get rights and content
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β-Adrenergic stimulation of adipose tissue increases mitochondrial density and activity (browning) that are associated with improved whole-body metabolism. Whereas chronically elevated levels of reactive oxygen species (ROS) in adipose tissue contribute to insulin resistance, transient ROS elevation stimulates physiological processes such as adipogenesis. Here, using a combination of biochemical and cell and molecular biology–based approaches, we studied whether ROS or antioxidant treatment affects β3-adrenergic receptor (β3-AR) stimulation–induced adipose tissue browning. We found that β3-AR stimulation increases ROS levels in cultured adipocytes, but, unexpectedly, pretreatment with different antioxidants (N-acetylcysteine, vitamin E, or GSH ethyl ester) did not prevent this ROS increase. Using fluorescent probes, we discovered that the antioxidant treatments instead enhanced β3-AR stimulation–induced mitochondrial ROS production. This pro-oxidant effect of antioxidants was, even in the absence of β3-AR stimulation, associated with decreased oxygen consumption and increased lactate production in adipocytes. We observed similar antioxidant effects in WT mice: N-acetylcysteine blunted β3-AR stimulation–induced browning of white adipose tissue and reduced mitochondrial activity in brown adipose tissue even in the absence of β3-AR stimulation. Furthermore, N-acetylcysteine increased the levels of peroxiredoxin 3 and superoxide dismutase 2 in adipose tissue, indicating increased mitochondrial oxidative stress. We interpret this negative impact of antioxidants on oxygen consumption in vitro and adipose tissue browning in vivo as essential adaptations that prevent a further increase in mitochondrial ROS production. In summary, these results suggest that chronic antioxidant supplementation can produce a paradoxical increase in oxidative stress associated with mitochondrial dysfunction in adipocytes.

reactive oxygen species (ROS)
adipose tissue
adrenergic receptor
antioxidant
vitamin E
mitochondria
oxidative stress
adipocyte
metabolism
browning
glutathione
N-acetylcysteine

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This work was supported by Swedish Research Council Grants 2012-1601, 2013-7107, and 2017-00792; a Novo Nordisk Foundation Excellence project grant; VINNOVA (Swedish Governmental Agency for Innovation Systems); the Swedish Diabetes Foundation; the Diabetes Wellness Research Foundation; the Åke Wiberg Foundation; the IngaBritt and Arne Lundberg Foundation; the Magnus Bergvall Foundation; and the European Union’s Seventh Framework Programme (FP7/2007–2013, Grant 607842). The authors declare that they have no conflicts of interest with the contents of this article.

This article contains Figs. S1–S5.