The Nrf1 and Nrf2 (also known as NFE2L1 and NFE2L2) transcription factors are critical regulators of genes involved in defense against oxidative stress. Previous studies have suggested 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 loss of either Nrf1 or Nrf2 results in a lean phenotype. Resistance to diet-induced obesity in Nrf2−/− mice is associated with a 20-30% increase in energy expenditure. This increase in whole animal energy expenditure is mirrored in the white adipose tissue of Nrf2−/− animals, which exhibit greater oxygen consumption in isolated tissue explants. Nrf2−/− WAT showed a greater than two-fold increase in Ucp1 gene expression along with increased expression of a variety of brown adipose tissue markers. Cell data mirrored that of animals with oxygen consumption increased nearly 2.5 fold in Nrf2 deficient fibroblasts. Oxidative stress induced by glucose oxidase resulted in increased Ucp1 expression and oxygen consumption. Conversely, antioxidant chemicals, such as N-acetylcysteine and MnTBAP, and SB203580, a known suppressor of Ucp1 expression, decreased Ucp1 and oxygen consumption in Nrf2 deficient fibroblasts. Examination of animals deficient in Nrf1 specifically in adipose tissue showed similar findings with increased expression of UCP1 and brown adipose tissue genes in the white adipose tissue. Additionally, Nrf1 deficient mice expressed higher levels of Metrnl1, a factor associated with increased Ucp1 levels. These findings suggest that modulating Nrf1 and Nrf2 levels in adipose tissue may be a novel means to regulate energy balance as a treatment of obesity and related clinical disorders.
|Advisor:||Chan, Jefferson Y.|
|Commitee:||Andersen, Bogi, Edwards, Robert|
|School:||University of California, Irvine|
|Department:||Biomedical Sciences - Ph.D.|
|School Location:||United States -- California|
|Source:||DAI-B 77/10(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology|
|Keywords:||Adipose tissue, Antioxidant, Oxidative stress, Reactive oxygen species, Uncoupling protein|
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