Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity

• Published in: International Journal of Obesity 2012-12, Vol.36 (12), p.1503-1513
• Main Authors: Li, Y, Mouche, S, Sajic, T, Veyrat-Durebex, C, Supale, R, Pierroz, D, Ferrari, S, Negro, F, Hasler, U, Feraille, E, Moll, S, Meda, P, Deffert, C, Montet, X, Krause, K-H, Szanto, I
• Format: Article
• Language: English
• Subjects: 631/208/727/2000; 631/443/319/1557; 631/443/319/1642/393; Ablation; Adipocytes; Adipocytes - metabolism; Adipose tissue; Adipose Tissue - pathology; Adiposity; Animals; Biological and medical sciences; Blotting, Western; Body fat; Body weight; Development and progression; Diet; Diet, High-Fat; Energy efficiency; Epidemiology; Fatty acids; Fatty Acids - blood; Fatty Liver - metabolism; Geriatrics; Glucose; Glucose Tolerance Test; Health aspects; Health Promotion and Disease Prevention; Homeostasis; Hypoxia; Insulin Resistance; Internal Medicine; Liver; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; NADP (Coenzyme); NADPH Oxidase 4; NADPH Oxidases - metabolism; Obesity; Obesity - metabolism; original-article; Oxidases; Oxidation; Physiological aspects; Protons; Public Health; Real-Time Polymerase Chain Reaction; Sensors; Up-Regulation; Weight Gain
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2011.279

OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo. DESIGN: Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice. RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid β-oxidation. CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis.