Effects of varying degrees of intermittent hypoxia on proinflammatory cytokines and adipokines in rats and 3T3-L1 adipocytes

PLoS One. 2014 Jan 21;9(1):e86326. doi: 10.1371/journal.pone.0086326. eCollection 2014.


Objectives: Intermittent hypoxia (IH), resulted from recurring episodes of upper airway obstruction, is the hallmark feature and the most important pathophysiologic pathway of obstructive sleep apnea (OSA). IH is believed to be the most important factor causing systemic inflammation. Studies suggest that insulin resistance (IR) is positively associated with OSA. In this study, we hypothesized that the recurrence of IH might result in cellular and systemic inflammation, which was manifested through the levels of proinflammatory cytokines and adipokines after IH exposure, and because IR is linked with inflammation tightly, this inflammatory situation may implicate an IR status.

Methods: We developed an IH 3T3-L1 adipocyte and rat model respectively, recapitulating the nocturnal oxygen profile in OSA. In IH cells, nuclear factor kappa B (NF-κB) DNA binding reactions, hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (Glut-1), necrosis factor alpha (TNF-α), interleukin (IL) -6, leptin, adiponectin mRNA transcriptional activities and protein expressions were measured. In IH rats, blood glucose, insulin, TNF-α, IL-6, leptin and adiponectin levels were analyzed.

Results: The insulin and blood glucose levels in rats and NF-κB DNA binding activities in cells had significantly statistical results described as severe IH>moderate IH>mild IH>sustained hypoxia>control. The mRNA and protein levels of HIF-1α and Glut-1 in severe IH group were the highest. In cellular and animal models, both the mRNA and protein levels of TNF-α, IL-6 and leptin were the highest in severe IH group, when the lowest in severe IH group for adiponectin.

Conclusions: Oxidative stress and the release of pro-inflammatory cytokines/adipokines, which are the systemic inflammatory markers, are associated with IH closely and are proportional to the severity of IH. Because IR and glucose intolerance are linked with inflammation tightly, our results may implicate the clinical relationships between OSA and IR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Adipokines / blood
  • Adipokines / metabolism*
  • Adiponectin / blood
  • Adiponectin / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Cytokines / metabolism*
  • Glucose Transporter Type 1 / metabolism
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inflammation / metabolism*
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Resistance / physiology
  • Interleukin-6 / blood
  • Interleukin-6 / metabolism
  • Leptin / blood
  • Leptin / metabolism
  • Models, Animal
  • NF-kappa B / metabolism
  • Oxidative Stress / physiology
  • Oxygen / metabolism
  • Rats
  • Sleep Apnea, Obstructive / blood
  • Sleep Apnea, Obstructive / metabolism
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / metabolism


  • Adipokines
  • Adiponectin
  • Blood Glucose
  • Cytokines
  • Glucose Transporter Type 1
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin
  • Interleukin-6
  • Leptin
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Oxygen

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (81270144, 30800507, 81170071), by grants from the Natural Science Foundation of Tianjin City (13JCYBJC22400, 13JCYBJC40000) and by grants from Tianjin Municipal Science and Technology Commission grant (# 09ZCZDSF04500). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.