Abstract
The NRF2 (also known as NFE2L2) transcription factor is a critical regulator of genes involved in defense against oxidative stress. Previous studies suggest thatNrf2plays a role in adipogenesisin vitro, and deletion of theNrf2gene protects against diet-induced obesity in mice. Here, we demonstrate that resistance to diet-induced obesity inNrf2(-/-)mice is associated with a 20-30% increase in energy expenditure. Analysis of bioenergetics revealed thatNrf2(-/-)white adipose tissues exhibit greater oxygen consumption. White adipose tissue showed a >2-fold increase inUcp1gene expression. Oxygen consumption is also increased nearly 2.5-fold inNrf2-deficient fibroblasts. Oxidative stress induced by glucose oxidase resulted in increasedUcp1expression. Conversely, antioxidant chemicals (such asN-acetylcysteine and Mn(III)tetrakis(4-benzoic acid)porphyrin chloride) and SB203580 (a known suppressor ofUcp1expression) decreasedUcp1and oxygen consumption inNrf2-deficient fibroblasts. These findings suggest that increasing oxidative stress by limitingNrf2function in white adipocytes may be a novel means to modulate energy balance as a treatment of obesity and related clinical disorders.
Highlights
Obesity is characterized by excess adipose tissue mass, and it is associated with various chronic diseases, including type 2 diabetes, hypertension, atherosclerosis, and cancer
Nrf2Ϫ/Ϫ Mice Are Resistant to High Fat Diet-induced Obesity—The body weights of wild type and Nrf2Ϫ/Ϫ male mice were indistinguishable at 12 weeks of age when fed a standard chow diet (Fig. 1A)
A comparison of adipose tissue mass normalized to lean body mass measured by EchoMRI showed that Nrf2Ϫ/Ϫ mice exposed to a high fat diet had 50% less wholebody fat compared with wild type mice
Summary
Reagents—Dulbecco’s modified Eagle’s medium (DMEM), ␣-minimum essential medium, fetal bovine serum (FBS), L-glutamine, penicillin, streptomycin, CM-H2DCFDA, MitoTracker Green FM, nanoyl-acridine orange, and Superscript III reverse transcriptase were purchased from Invitrogen. Glucose oxidase, butylated hydroxyanisole (BHA), and anti--actin antibody (A1978) were purchased from Sigma. TRIzol RNA reagent, 2ϫ FastStart SYBR Green Master mix, was purchased from Roche Applied Science. Mice were housed on 12-h light and dark cycles under controlled environmental settings (23 Ϯ 1 °C), with free access to food and water. Fasting serum triglyceride levels were analyzed with a serum triglyceride kit according to the manufacturer’s instructions (Sigma), and serum concentrations of insulin were determined using the Ultra Sensitive Mouse Insulin ELISA Kit from Crystal Chem (Downers Grove, IL). RNA Isolation and Quantitative Real-time PCR—RNA was extracted using TRIzol RNA reagent and further purified using the RNeasy MinElute Cleanup Kit. cDNA synthesis was generated with a Superscript III first-strand synthesis kit according to the manufacturer’s recommendation.
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