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Animal Models

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

International Journal of Obesity volume 36, pages 1503–1513 (2012)Cite this article

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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.

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.

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Acknowledgements

This work was supported by The Swiss National Science Foundation (Grant No. 3100A0-122327) to IS, 3100A0-103725 to KHK and 310030-141162 to PM. We thank F Rohner-Jeanrenaud and C Wollheim (University of Geneva) for helpful discussions and critical reading of the manuscript. We are grateful to C Chapponnier (University of Geneva) for providing the α-SMA antibody. We thank our collaborators at the University of Geneva: Olivier Plastre and Dorothee Rigo for the excellent technical assistance, Sergei Startcsik for the computer-assisted analysis of adipose tissue, Patrick Descombes and Didier Chollet for the miRNA analysis and Annelise Wohlwend for help with histological evaluation.

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Author notes

  1. Y Li

    Present address: 7Current address: Beijing Hospital, Beijing, P.R China,

  2. Y Li and S Mouche: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland

    Y Li, S Mouche, T Sajic, R Supale, U Hasler, E Feraille, P Meda, X Montet & I Szanto

  2. Department of Medical Specialties, University of Geneva, Geneva, Switzerland

    C Veyrat-Durebex, D Pierroz & S Ferrari

  3. Department of Rehabilitation and Geriatrics, University of Geneva, Geneva, Switzerland

    D Pierroz, S Ferrari & I Szanto

  4. Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland

    F Negro & K-H Krause

  5. Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland

    F Negro, S Moll & K-H Krause

  6. Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

    C Deffert

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Li, Y., Mouche, S., Sajic, T. et al. Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity. Int J Obes 36, 1503–1513 (2012). https://doi.org/10.1038/ijo.2011.279

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