Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes
Journal article, 2018

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 glutathione 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 absence of β3-AR stimulation, associated with decreased oxygen consumption and increased lactate production in adipocytes. We observed similar antioxidant effects in wildtype 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.

Glutathione

N-acetylcysteine

metabolism

reactive oxygen species (ROS)

adipocyte

adipose tissue

adrenergic receptor

oxidative stress

mitochondria

antioxidant

vitamin E

Browning

Author

Eduard Peris

University of Gothenburg

Peter Micallef

University of Gothenburg

Alexandra Paul

Chalmers, Biology and Biological Engineering, Chemical Biology

Vilborg Palsdottir

University of Gothenburg

Annika Enejder

Chalmers, Biology and Biological Engineering, Chemical Biology

Marco Bauzá-Thorbrügge

University of Gothenburg

Charlotta S Olofsson

University of Gothenburg

Ingrid Wernstedt Asterholm

University of Gothenburg

Journal of Biological Chemistry

0021-9258 (ISSN) 1083-351X (eISSN)

Vol. 294 7 2340-2352

Subject Categories

Cell and Molecular Biology

Physiology

Medical Biotechnology

DOI

10.1074/jbc.RA118.004253

PubMed

30559295

More information

Latest update

7/19/2019