title: Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Mouche
authors.forename: T
authors.initials: T
authors.lastname: Sajic
authors.forename: C
authors.initials: C
authors.lastname: Veyrat-Durebex
authors.forename: R
authors.initials: R
authors.lastname: Supale
authors.forename: D
authors.initials: D
authors.lastname: Pierroz
authors.forename: S
authors.initials: S
authors.lastname: Ferrari
authors.forename: F
authors.initials: F
authors.lastname: Negro
authors.forename: U
authors.initials: U
authors.lastname: Hasler
authors.forename: E
authors.initials: E
authors.lastname: Feraille
authors.forename: S
authors.initials: S
authors.lastname: Moll
authors.forename: P
authors.initials: P
authors.lastname: Meda
authors.forename: C
authors.initials: C
authors.lastname: Deffert
authors.forename: X
authors.initials: X
authors.lastname: Montet
authors.forename: K-H
authors.initials: KH
authors.lastname: Krause
authors.forename: I
authors.initials: I
authors.lastname: Szanto
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000473:pathology*; D050154:Adiposity; D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000097:blood; D005234:Fatty Liver / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation; D015430:Weight Gain
chemical_list: D005227:Fatty Acids; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse