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

OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redoxhomeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocytedifferentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating therole 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 12weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzedand compared with similarly treated wild-type mice.RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible todiet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation andhypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissuehypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lackof proper upregulation of mitochondrial fatty acid b-oxidation.CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate ananti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-inducedobesity, insulin resistance and hepatosteatosis.International Journal of Obesity advance online publication, 20 March 2012; doi:10.1038/ijo.2011.279Keywords: NOX4; adipocyte differentiation; high-fat dietINTRODUCTIONNADPH oxidases are pro-oxidant enzymes whose main cellularfunction is the production of reactive oxygen species (ROS). Thebest renowned member of this family is the phagocyte NADPHoxidase (gp91