A Role of Stress Sensor Nrf2 in Stimulating Thermogenesis and Energy Expenditure

Abstract

During chronic cold stress, thermogenic adipocytes generate heat through uncoupling of mitochondrial respiration from ATP synthesis. Recent discovery of various dietary phytochemicals, endogenous metabolites, synthetic compounds, and their molecular targets for stimulating thermogenesis has provided promising strategies to treat or prevent obesity and its associated metabolic diseases. Nuclear factor E2 p45-related factor 2 (Nrf2) is a stress response protein that plays an important role in obesity and metabolisms. However, both Nrf2 activation and Nrf2 inhibition can suppress obesity and metabolic diseases. Here, we summarized and discussed conflicting findings of Nrf2 activities accounting for part of the variance in thermogenesis and energy metabolism. We also discussed the utility of Nrf2-activating mechanisms for their potential applications in stimulating energy expenditure to prevent obesity and improve metabolic deficits.

Keywords: Nrf2; energy expenditure; metabolic diseases; obesity; thermogenesis; uncoupling.

Figure 1

Cellular stresses activate Nrf2 to induce defense systems, reduce body weight, and increase energy expenditure. Schematic diagram of Nrf2-induced responses against various cellular stresses. Cold exposure, physical exercise, food intake, and xenobiotic chemicals activate Nrf2 to transcribe its target genes involved in antioxidation, detoxification, mitochondrial biogenesis, and energy expenditure. ROS can be produced by cold, exercise, high energy diets, and chemical activators that can disrupt Kelch-like ECH-associated protein 1 (Keap1) and Nrf2 interaction to increase Nrf2 abundance and subsequent nuclear translocation of Nrf2. In the nucleus, Nrf2 forms a heterodimer with a small Maf protein and binds to antioxidant response element (ARE) in the promoter region to drive transcription of antioxidative genes. Its target genes include glutamate-cysteine ligase catalytic subunit (GCLC), glutathione reductase, ABCC-family efflux transporter genes, NAD(P)H quinone oxidoreductase1 (NQO1), heme oxygenase1 (HO1), and possibly mitochondrial genes including nuclear respiratory factor 1 (Nrf1), Peroxisome proliferator-activated receptor-gamma coactivator-1a (Pgc1α), and uncoupling protein 1 (Ucp1).

Figure 2

Comparative effects of Nrf2 activation and Nrf2 inhibition on defense responses, weight reduction, and increases of energy expenditure. Schematic diagram shows effects of Nrf2—gain and loss—of function on energy expenditure and weight reduction. Various cellular stresses can activate Nrf2 to provide defense mechanisms in antioxidation and detoxification. Nrf2 inhibition increases energy expenditure and decreases weight gain in a high calorie diet feeding. However, Nrf2 inhibition potentially fails to protect cells from oxidative/electrophilic stress and inflammatory insults. By contrast, chemical Nrf2 activators can stimulate mitochondrial biogenesis in tissues while Nrf2 inhibition impairs mitochondrial biogenesis and energy expenditure.