Adipose Deficiency of Nrf2 in ob/ob Mice Results in Severe Metabolic Syndrome

Abstract

Nuclear factor E2–related factor 2 (Nrf2) is a transcription factor that functions as a master regulator of the cellular adaptive response to oxidative stress. Our previous studies showed that Nrf2 plays a critical role in adipogenesis by regulating expression of CCAAT/enhancer-binding protein β and peroxisome proliferator–activated receptor γ. To determine the role of Nrf2 in the development of obesity and associated metabolic disorders, the incidence of metabolic syndrome was assessed in whole-body or adipocyte-specific Nrf2-knockout mice on a leptin-deficient ob/ob background, a model with an extremely positive energy balance. On the ob/ob background, ablation of Nrf2, globally or specifically in adipocytes, led to reduced white adipose tissue (WAT) mass, but resulted in an even more severe metabolic syndrome with aggravated insulin resistance, hyperglycemia, and hypertriglyceridemia. Compared with wild-type mice, WAT of ob/ob mice expressed substantially higher levels of many genes related to antioxidant response, inflammation, adipogenesis, lipogenesis, glucose uptake, and lipid transport. Absence of Nrf2 in WAT resulted in reduced expression of most of these factors at mRNA or protein levels. Our findings support a novel role for Nrf2 in regulating adipose development and function, by which Nrf2 controls the capacity of WAT expansion and insulin sensitivity and maintains glucose and lipid homeostasis.

Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis, fibrosis, and oxidative stress in high-fat diet-fed mice

“…Previous studies demonstrated that Nrf2 inhibited onset and progression of NAFLD caused by HFD by activation of cellular antioxidant defense system (Okada et al 2013). Moreover, Nrf2 showed great ability in the regulation of lipogenesis, lipolysis (Xue et al 2013), and fibrosis (Shimozono et al Fig. 4 Effect of MLE on plasma and hepatic oxidative stress-related markers in high-fat diet-induced obese mice.…”

“…Previous studies demonstrated that Nrf2 inhibited onset and progression of NAFLD caused by HFD through activation of antioxidant defense system (Okada et al 2013). Nrf2 showed the ability to regulate lipogenesis, lipolysis (Xue et al 2013), and fibrosis (Shimozono et al 2013) in NAFLD. In addition, Nrf2 can decrease the levels of oxidative stress by induction of defensive antioxidant enzymes such as HO-1 (Su et al 2013) and modulate lipid metabolism and fibrosis in liver.…”

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

“…Additional studies utilizing the ob/ob genetic model of obesity have yielded varied results. Nrf2 knock-out animals crossed into the ob/ob mouse background, using either a whole animal or fatspecific Nrf2 knock-out, demonstrated that loss of Nrf2 resulted in decreased adipose tissue mass yet aggravated insulin resistance, hyperglycemia, and hypertriglyceridemia (81). This seems to demonstrate that in genetic models of obesity and diabetes, the results of Nrf2 modulation can vary drastically, depending on the specific conditions of the model.…”

Multiple roles of Nrf2-Keap1 signaling

“…Targeted deletion of Nrf2 in mice causes developmental defects in adipogenesis and hematopoiesis, in addition to many oxidative stress defects upon treatment with xenobiotic agents. [19][20][21][22][23] Nrf2 can directly bind and activate adipogenic genes such as peroxisome proliferator-activated receptor γ (Pparγ) 21 and retinoid X receptor α (RXRA). 24 Nrf2 controls hematopoietic stem cell functions through transcriptional regulation of CXCR4.…”