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Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes

Journal article
Authors Eduard Peris
Peter Micallef
A. Paul
Vilborg Palsdottir
A. Enejder
Marco Bauzá-Thorbrügge
Charlotta S Olofsson
Ingrid Wernstedt Asterholm
Published in Journal of Biological Chemistry
Volume 294
Issue 7
Pages 2340-2352
Publication year 2019
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Physiology
Pages 2340-2352
Language en
Links dx.doi.org/10.1074/jbc.RA118.004253
Keywords reactive oxygen species (ROS), adipose tissue, adrenergic receptor, antioxidant, vitamin E, mitochondria, oxidative stress, adipocyte, metabolism, browning, glutathione, N-acetylcysteine, increased oxidative stress, glutathione, ros, differentiation, expression, nrf2, cell, Biochemistry & Molecular Biology
Subject categories Biochemistry and Molecular Biology

Abstract

beta-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 beta 3-adrenergic receptor (beta 3-AR) stimulation-induced adipose tissue browning. We found that beta 3-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 beta 3-AR stimulation-induced mitochondrial ROS production. This pro-oxidant effect of antioxidants was, even in the absence of beta 3-AR stimulation, associated with decreased oxygen consumption and increased lactate production in adipocytes. We observed similar antioxidant effects in WT mice: N-acetylcysteine blunted beta 3-AR stimulation-induced browning of white adipose tissue and reduced mitochondrial activity in brown adipose tissue even in the absence of beta 3-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.

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