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Sleep-disordered breathing, circulating exosomes, and insulin sensitivity in adipocytes

International Journal of Obesity volume 42, pages 1127–1139 (2018)Cite this article

Subjects

Abstract

Background:

Sleep-disordered-breathing (SDB), which is characterized by chronic intermittent hypoxia (IH) and sleep fragmentation (SF), is a prevalent condition that promotes metabolic dysfunction, particularly among patients suffering from obstructive hypoventilation syndrome (OHS). Exosomes are generated ubiquitously, are readily present in the circulation, and their cargo may exert substantial functional cellular alterations in both physiological and pathological conditions. However, the effects of plasma exosomes on adipocyte metabolism in patients with OHS or in mice subjected to IH or SF mimicking SDB are unclear.

Methods:

Exosomes from fasting morning plasma samples from obese adults with polysomnographically-confirmed OSA before and after 3 months of adherent CPAP therapy were assayed. In addition, C57BL/6 mice were randomly assigned to (1) sleep control (SC), (2) sleep fragmentation (SF), and (3) intermittent hypoxia (HI) for 6 weeks, and plasma exosomes were isolated. Equivalent exosome amounts were added to differentiated adipocytes in culture, after which insulin sensitivity was assessed using 0 nM and 5 nM insulin-induced pAKT/AKT expression changes by western blotting.

Results:

When plasma exosomes were co-cultured and internalized by human naive adipocytes, significant reductions emerged in Akt phosphorylation responses to insulin when compared to exosomes obtained after 24 months of adherent CPAP treatment (n = 24; p < 0.001), while no such changes occur in untreated patients (n = 8). In addition, OHS exosomes induced significant increases in adipocyte lipolysis that were attenuated after CPAP, but did not alter pre-adipocyte differentiation. Similarly, exosomes from SF- and IH-exposed mice induced attenuated p-AKT/total AKT responses to exogenous insulin and increased glycerol content in naive murine adipocytes, without altering pre-adipocyte differentiation.

Conclusions:

Using in vitro adipocyte-based functional reporter assays, alterations in plasma exosomal cargo occur in SDB, and appear to contribute to adipocyte metabolic dysfunction. Further exploration of exosomal miRNA signatures in either human subjects or animal models and their putative organ and cell targets appears warranted.

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Acknowledgements

This study was supported by National Institutes of Health grant HL130984 (to LKG), Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo) grant PI050402, Spanish Respiratory Foundation 2005 (FEPAR) and Air Liquide Spain.

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Authors and Affiliations

  1. Section of Pediatric Sleep Medicine, Department of Pediatrics, Biological Sciences Division, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA

    Abdelnaby Khalyfa, David Gozal, Zhuanghong Qiao & Leila Kheirandish-Gozal

  2. San Pedro de Alcántara Hospital, Cáceres, Spain

    Juan F Masa & Francisco J Gómez de Terreros

  3. Centro de Investigación Biomédica en Red de enfermedades respiratorias (CIBERES), Madrid, Spain

    Juan F Masa, Jaime Corral, Sergi Marti & Francisco J Gómez de Terreros

  4. Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza, Spain

    José Maria Marin

  5. CIBER Enfermedades Respiratorias (CIBERES), Zaragoza, Spain

    José Maria Marin

  6. Sleep Unit and Respiratory Department, Alava University Hospital IRB, Vitoria, Spain

    Jaime Corral & Carlos Egea

  7. Valdecilla Hospital, Santander, Spain

    Mónica González

  8. Valld’Hebron Hospital, Barcelona, Spain

    Sergi Marti

  9. Virgen del Puerto Hospital, Plasencia, Spain

    M-Ángeles Sánchez-Quiroga

  10. Extremadura University, Caceres, Spain

    F Javier Barca

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Khalyfa, A., Gozal, D., Masa, J.F. et al. Sleep-disordered breathing, circulating exosomes, and insulin sensitivity in adipocytes. Int J Obes 42, 1127–1139 (2018). https://doi.org/10.1038/s41366-018-0099-9

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