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 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.