Correction of intermittent hypoxia reduces inflammation in obese subjects with obstructive sleep apnea

Abstract

Background: In obese subjects with obstructive sleep apnea (OSA), chronic intermittent hypoxia (CIH) may be linked to systemic and adipose tissue inflammation.

Methods: We obtained abdominal subcutaneous adipose tissue biopsies from OSA and non-OSA obese (BMI > 35) subjects at baseline and after 24 weeks (T1) of weight-loss intervention plus continuous positive airway pressure (c-PAP) or weight-loss intervention alone, respectively. OSA subjects were grouped according to good (therapeutic) or poor (subtherapeutic) adherence to c-PAP.

Results: At baseline, anthropometric and metabolic parameters, serum cytokines, and adipose tissue mRNA levels of obesity-associated chemokines and inflammatory markers were not different in OSA and non-OSA subjects. At T1, body weight was significantly reduced in all groups. Serum concentrations of IL-2, IL-4, IL-6, MCP-1, PDGFβ, and VEGFα were reduced by therapeutic c-PAP in OSA subjects and remained unaltered in non-OSA and subtherapeutic c-PAP groups. Similarly, adipose tissue mRNA levels of macrophage-specific (CD68, CD36) and ER stress (ATF4, CHOP, ERO-1) gene markers, as well as of IL-6, PDGFβ, and VEGFα, were decreased only in the therapeutic c-PAP group.

Conclusion: CIH does not represent an additional factor increasing systemic and adipose tissue inflammation in morbid obesity. However, in subjects with OSA, an effective c-PAP therapy improves systemic and obesity-associated inflammatory markers.

Funding: Ministero dell'Università e della Ricerca and Progetti di Rilevante Interesse Nazionale.

Keywords: Adipose tissue; Cytokines; Metabolism; Pulmonology; hypoxia.

Figure 1. Study design.

OSA, obstructive sleep apnea; c-PAP, continuous positive airway pressure.

Figure 2. Baseline serum cytokine concentrations in non-OSA, OSA therapeutic c-PAP, and OSA subtherapeutic c-PAP obese subjects.

Circulating levels were assessed in non-OSA (white bars), OSA therapeutic c-PAP (black bars), and OSA subtherapeutic c-PAP (gray bars) obese subjects at baseline. Serum levels (pg/ml) were determined by the Bio-Plex assay, as described in the Methods. Results are mean ± SEM (n = 2 measurements for each subject; n = 15 non-OSA, n = 16 OSA therapeutic c-PAP; and n = 15 OSA subtherapeutic c-PAP). Differences among groups were assessed with 1-way ANOVA statistical analysis. OSA, obstructive sleep apnea; c-PAP, continuous positive airway pressure.

Figure 3. Baseline mRNA expression of ER stress and inflammatory genes in subcutaneous adipose tissue from non-OSA, OSA therapeutic c-PAP, and OSA subtherapeutic c-PAP obese subjects.

Subcutaneous adipose tissue biopsies were obtained from non-OSA (white bars), OSA therapeutic c-PAP (black bars), and OSA subtherapeutic c-PAP (gray bars) obese subjects at baseline. mRNA levels of ER stress and inflammatory genes were determined by quantitative RT-PCR and normalized to 18S rRNA. Results are mean ± SEM of values in adipose tissue (n = 2 measurements for each subject; n = 15 non-OSA; n = 16 OSA therapeutic c-PAP; and n = 15 OSA subtherapeutic c-PAP). Differences among groups were assessed with 1-way ANOVA statistical analysis. ER, endoplasmic reticulum; OSA, obstructive sleep apnea; c-PAP, continuous positive airway pressure.

Figure 4. Effects of intervention on circulating cytokines.

Serum levels of IL-2, IL-4, IL-6, IL-10, MCP-1, PDGFβ, VEGFα, and RANTES were assessed in non-OSA (white bars), OSA therapeutic c-PAP (black bars), and OSA subtherapeutic c-PAP (gray bars) subjects before and after 24 weeks of treatment, as indicated in Figure 1. Absolute serum levels (pg/ml) were determined by Bio-Plex assay, as described in the Methods. Results shown are mean ± SEM of changes versus baseline (n = 2 measurements for each subject; n = 15 non-OSA; n = 16 OSA therapeutic c-PAP; and n = 15 OSA subtherapeutic c-PAP). *P < 0.05 vs. baseline (1-sample t test); ^#P < 0.05 vs. non-OSA and OSA subtherapeutic c-PAP (1-way ANOVA). OSA, obstructive sleep apnea; c-PAP, continuous positive airway pressure.

Figure 5. Effects of intervention on mRNA expression of ER stress and inflammatory genes in subcutaneous adipose tissue.

Subcutaneous adipose tissue biopsies were obtained in non-OSA (white bars), OSA therapeutic c-PAP (black bars), and OSA subtherapeutic c-PAP (gray bars) subjects before and after 24 weeks of treatment, as indicated in Figure 1. mRNA levels of ER stress and inflammatory genes were determined by quantitative RT-PCR and normalized to 18S rRNA. Results are mean ± SEM of changes versus baseline (n = 2 measurements for each subject; n = 15 non-OSA; n = 16 OSA therapeutic c-PAP; and n = 15 OSA subtherapeutic c-PAP). *P < 0.05 vs. baseline (1-sample t test). ^#P < 0.05 vs. non-OSA and OSA subtherapeutic c-PAP (1-way ANOVA). ER, endoplasmic reticulum; OSA, obstructive sleep apnea; c-PAP, continuous positive airway pressure.

Figure 6. Relationship between time of c-PAP use and systemic and adipose tissue inflammation.

Correlation between time of c-PAP use and serum levels of IL-4, PDGFβ, and VEGFα in OSA obese subjects (top). Correlation between time of c-PAP use and adipose tissue mRNA levels of CD36, CD68, and ERO1 in OSA obese subjects (bottom) (n = 16 OSA therapeutic c-PAP subjects; n = 15 OSA subtherapeutic c-PAP subjects). Statistical analysis was performed using Pearson correlation. OSA, obstructive sleep apnea; c-PAP, continuous positive airway pressure.

Figure 7. Proposed model of the effects of obesity, OSA, and c-PAP therapy on systemic and adipose tissue inflammation and cardiometabolic abnormalities.

OSA, obstructive sleep apnea; c-PAP, continuous positive airway pressure.