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J Biol Chem. 2019 Feb 15;294(7):2340-2352. doi: 10.1074/jbc.RA118.004253. Epub 2018 Dec 17.

Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes.

Author information

1
From the Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Box 432, SE-405 30 Gothenburg, Sweden and.
2
Division of Chemical Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.
3
From the Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Box 432, SE-405 30 Gothenburg, Sweden and IWA@neuro.gu.se.

Abstract

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.

KEYWORDS:

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

PMID:
30559295
PMCID:
PMC6378980
DOI:
10.1074/jbc.RA118.004253
[Indexed for MEDLINE]
Free PMC Article

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