Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

The NRF2 (also known as NFE2L2) transcription factor is a critical regulator of genes involved in defense against oxidative stress. Previous studies suggest that Nrf2 plays a role in adipogenesis in vitro, and deletion of the Nrf2 gene protects against diet-induced obesity in mice. Here, we demonstr...

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Bibliographic Details
Published in:The Journal of biological chemistry 2016-04, Vol.291 (14), p.7754-7766
Main Authors: Schneider, Kevin, Valdez, Joshua, Nguyen, Janice, Vawter, Marquis, Galke, Brandi, Kurtz, Theodore W., Chan, Jefferson Y.
Format: Article
Language:English
Subjects:
Adipogenesis
adipose tissue
Animals
antioxidant
Diet - adverse effects
Fibroblasts - metabolism
Fibroblasts - pathology
Free Radical Scavengers - pharmacology
Gene Expression Regulation
Ion Channels - biosynthesis
Ion Channels - genetics
Metabolism
Mice
Mice, Knockout
Mitochondrial Proteins - biosynthesis
Mitochondrial Proteins - genetics
NF-E2-Related Factor 2 - deficiency
Obesity - chemically induced
Obesity - genetics
Obesity - metabolism
Obesity - pathology
Oxidative Stress
Oxygen Consumption - drug effects
reactive oxygen species (ROS)
uncoupling protein
Uncoupling Protein 1
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Summary:The NRF2 (also known as NFE2L2) transcription factor is a critical regulator of genes involved in defense against oxidative stress. Previous studies suggest that Nrf2 plays a role in adipogenesis in vitro, and deletion of the Nrf2 gene protects against diet-induced obesity in mice. Here, we demonstrate that resistance to diet-induced obesity in Nrf2−/− mice is associated with a 20–30% increase in energy expenditure. Analysis of bioenergetics revealed that Nrf2−/− white adipose tissues exhibit greater oxygen consumption. White adipose tissue showed a >2-fold increase in Ucp1 gene expression. Oxygen consumption is also increased nearly 2.5-fold in Nrf2-deficient fibroblasts. Oxidative stress induced by glucose oxidase resulted in increased Ucp1 expression. Conversely, antioxidant chemicals (such as N-acetylcysteine and Mn(III)tetrakis(4-benzoic acid)porphyrin chloride) and SB203580 (a known suppressor of Ucp1 expression) decreased Ucp1 and oxygen consumption in Nrf2-deficient fibroblasts. These findings suggest that increasing oxidative stress by limiting Nrf2 function in white adipocytes may be a novel means to modulate energy balance as a treatment of obesity and related clinical disorders.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M115.673756