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NRF2 is essential for adaptative browning of white adipocytes
Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
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2023 (English)In: Redox Biology, E-ISSN 2213-2317, Vol. 68, article id 102951Article in journal (Refereed) Published
Abstract [en]

White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes. 

Place, publisher, year, edition, pages
Elsevier, 2023. Vol. 68, article id 102951
Keywords [en]
Adipose tissue, Lactate, N-acetylcysteine, NRF2, Redox stress
National Category
Physiology Endocrinology and Diabetes Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmacology and Toxicology
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-23363DOI: 10.1016/j.redox.2023.102951ISI: 001110673000001PubMedID: 37931470Scopus ID: 2-s2.0-85175560964OAI: oai:DiVA.org:his-23363DiVA, id: diva2:1812418
Note

CC BY 4.0 DEED

© 2023 The Authors

Correspondence Address: I. Wernstedt Asterholm; Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Medicinaregatan 11, PO Box 432, SE, 405 30, Sweden; email: IWA@neuro.gu.se

Available from: 2023-11-16 Created: 2023-11-16 Last updated: 2024-04-03Bibliographically approved

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Benrick, Anna

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