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  • Original Article
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Sleep fragmentation promotes NADPH oxidase 2-mediated adipose tissue inflammation leading to insulin resistance in mice

International Journal of Obesity volume 38, pages 619–624 (2014)Cite this article

Subjects

Abstract

Background:

Short sleep has been implicated in higher risk of obesity in humans, and is associated with insulin resistance. However, the effects of fragmented sleep (SF) rather than curtailed sleep on glucose homeostasis are unknown.

Methods:

Wild-type and NADPH oxidase 2 (Nox2) null male mice were subjected to SF or sleep control conditions for 3 days to 3 weeks. Systemic and visceral adipose tissue (VAT) insulin sensitivity tests, glucose tolerance test, fluorescence-activated cell sorting and immunohistochemistry for macrophages and its sub-types (M1 and M2), and Nox expression and activity were examined.

Results:

Here we show that SF in the absence of sleep curtailment induces time-dependent insulin resistance, in vivo and also in vitro in VAT. Oxidative stress pathways were upregulated by SF in VAT, and were accompanied by M1 macrophage polarization. SF-induced oxidative stress, inflammation and insulin resistance in VAT were completely abrogated in genetically altered mice lacking Nox2 activity.

conclusions:

These studies imply that SF, a frequent occurrence in many disorders and more specifically in sleep apnea, is a potent inducer of insulin resistance via activation of oxidative stress and inflammatory pathways, thereby opening the way for therapeutic strategies.

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Acknowledgements

DG is supported by National Institutes of Health grants HL65270 and HL86662. AK and SXLZ were supported by Comer Kids Classic grants.

Author contributions

SXLZ and AK performed the experiments and analyzed the data. YW conducted the experiments, analyzed the data, drafted portions of the manuscript and served as blinded observer. AC and FH performed GTT and ITT assays. AC and CH performed sleep recordings. BAN and MJB assisted with technical aspects of adipose tissue insulin sensitivity assays. ZQ performed the experiments, particularly immunohistochemistry. DG provided the conceptual design of the project, analyzed the data, drafted the manuscript and is responsible for the financial support of the project and the manuscript content. All authors have reviewed and approved the final version of the manuscript. DG is supported by National Institutes of Health grants HL-65270, HL-086662 and HL-107160. Dr Gozal is the guarantor of this work, had full access to all the data and takes full responsibility for the integrity of data and the accuracy of data analysis.

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Author notes

  1. S X L Zhang, A Khalyfa and Y Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Section of Pediatric Sleep Medicine, The University of Chicago, Chicago, IL, USA

    S X L Zhang, A Khalyfa, Y Wang, A Carreras, F Hakim, Z Qiao, C Hirotsu & D Gozal

  2. Department of Medicine, Biological Sciences Division, Section of Endocrinology, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA

    B A Neel & M J Brady

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  1. S X L Zhang
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Correspondence to D Gozal.

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Zhang, S., Khalyfa, A., Wang, Y. et al. Sleep fragmentation promotes NADPH oxidase 2-mediated adipose tissue inflammation leading to insulin resistance in mice. Int J Obes 38, 619–624 (2014). https://doi.org/10.1038/ijo.2013.139

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  • DOI: https://doi.org/10.1038/ijo.2013.139

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