Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes.
J Biol Chem
; 294(7): 2340-2352, 2019 02 15.
Article
em En
| MEDLINE
| ID: mdl-30559295
ABSTRACT
ß-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 ß3-adrenergic receptor (ß3-AR) stimulation-induced adipose tissue browning. We found that ß3-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 ß3-AR stimulation-induced mitochondrial ROS production. This pro-oxidant effect of antioxidants was, even in the absence of ß3-AR stimulation, associated with decreased oxygen consumption and increased lactate production in adipocytes. We observed similar antioxidant effects in WT mice N-acetylcysteine blunted ß3-AR stimulation-induced browning of white adipose tissue and reduced mitochondrial activity in brown adipose tissue even in the absence of ß3-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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Base de dados:
MEDLINE
Assunto principal:
Acetilcisteína
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Espécies Reativas de Oxigênio
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Estresse Oxidativo
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Adipócitos Marrons
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Mitocôndrias
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Antioxidantes
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2019
Tipo de documento:
Article