Abstract
BackgroundSleep-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.MethodsExosomes 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 5nM insulin-induced pAKT/AKT expression changes by western blotting.ResultsWhen plasma exosomes were co-cultured and internalized by human naïve 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 naïve murine adipocytes, without altering pre-adipocyte differentiation.ConclusionsUsing 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.
Highlights
Obesity is a major risk factor for the development of metabolic syndrome and insulin resistance, and is associated with an increased risk of disability and morbidity [1, 2]
When plasma exosomes were co-cultured and internalized by human naïve adipocytes, significant reductions emerged in Akt phosphorylation responses to insulin when compared to exosomes obtained after 24 months of adherent continuous positive airway pressure (CPAP) treatment (n=24; p
Flow cytometry of isolated exosomes derived from human obstructive hypoventilation syndrome (OHS), obstructive sleep apnea (OSA), or from murine models of OSA revealed the presence of tetraspanins, targeting/adhesion, and antigen presentation markers as anticipated from highly purified (>95%) exosome fractions
Summary
Obesity is a major risk factor for the development of metabolic syndrome and insulin resistance, and is associated with an increased risk of disability and morbidity [1, 2]. It is estimated that 90% of patients with OHS have obstructive sleep apnea (OSA) 6. The exact prevalence of OHS in the community is unclear, but is estimated to be approximately 0.15–0.6% of the general population 7, 8, 9–20% of referred obese patients, and up to 42% of referrals when BMI is >35 kg/m2 9–11. A paradoxical protective effect of OHS on cardiovascular function has been recently suggested 12, such that it is yet unclear how OHS and OSA in obese patients differ as far as their potential contributions to end-organ morbidity. Sleep-disordered-breathing (SDB), which is characterized by chronic intermittent hypoxia (IH) and sleep fragmentation (SF), is a prevalent condition that promotes metabolic dysfunction, among patients suffering from obstructive hypoventilation syndrome (OHS). The effects of plasma exosomes on adipocyte metabolism in patients with OHS or in mice subjected to IH or SF mimicking SDB are unclear
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