Chronic hypoxaemia and gender status modulate adiponectin plasmatic level and its multimer proportion in severe COPD patients: new endotypic presentation?

BACKGROUND: Disease progression in COPD patient is associated to lung function decline, leading to a higher risk of hypoxaemia and associated comorbidities, notably cardiovascular diseases (CVD). Adiponectin (Ad) is an adipokine with cardio-protective properties. In COPD patients, conflicting results were previously reported regarding Ad plasmatic (Adpl) level, probably because COPD is a heterogeneous disease with multifactorial influence. Among these factors, gender and hypoxaemia could interact in a variety of ways with Ad pathway. Therefore, we postulated that these components could influence Adpl level and its multimers in COPD patients and contribute to the appearance of a distinct endotype associated to an altered CVD risk. METHODS: One hundred COPD patients were recruited: 61 were men and 39 were women. Patients who were not severely hypoxemic were allocated to non-hypoxemic group which included 46 patients: 27 men and 19 women. Hypoxemic group included 54 patients: 34 men and 20 women. For all patients, Adpl level and proportion of its different forms were measured. Differences between groups were evaluated by Rank-Sum tests. The relationship between these measures and BMI, blood gas analysis (PaO2, PaCO2), or lung function (FEV1, FEV1/FVC, TLCO, TLC, RV) were evaluated by Pearson correlation analysis. RESULTS: Despite similar age, BMI and obstruction severity, women had a higher TLC and RV (median: TLC = 105%; RV = 166%) than men (median: TLC = 87%; RV = 132%). Adpl level was higher in women (median = 11,152 ng/ml) than in men (median = 10,239 ng/ml) and was negatively associated with hyperinflation (R = - 0,43) and hypercapnia (R = - 0,42). The proportion of the most active forms of Ad (HMW) was increased in hypoxemic women (median = 10%) compared with non-hypoxemic women (median = 8%) but was not modulated in men. CONCLUSION: COPD pathophysiology seemed to be different in hypoxemic women and was associated to Ad modulations. Hyperinflation and air-trapping in association with hypercapnia and hypoxaemia, could contribute to a modulation of Adpl level and of its HMW forms. These results suggest the development of a distinct endotypic presentation, based on gender.

Sustained Intermittent Hypoxemia Induces Adiponectin Oligomers Redistribution and a Tissue-Specific Modulation of Adiponectin Receptor in Mice.

Introduction: Hypoxemia is a critical component of several respiratory diseases and is known to be involved in the processes underlying co-morbidities associated to such disorders, notably at the cardiovascular level. Circulating level of Adiponectin (Ad), known as a metabolic regulator and cardio-protective hormone was previously suggested to be reduced by hypoxia but consequences of such variation are unclear. The evaluation of the specific effect of hypoxemia on Ad forms and receptors could improve the understanding of the involvement of Ad axis in hypoxemia-related diseases. Methods: Ad-pathway components were investigated in a murine model of sustained intermittent hypoxemia (FiO2 10%, 8 h/day, 35 days). Results: Sustained intermittent hypoxemia (SIH) induced a redistribution of Ad multimers in favor of HMW forms, without change in total plasmatic level. Mice submitted to hypoxia also exhibited tissue-specific modification of adiporeceptor (AdipoR) protein level without mRNA expression change. A decreased AdipoR2 abundance was observed in skeletal muscle and heart whereas AdipoR1 level was only reduced in muscle. No change was observed in liver regarding AdipoR. Lipid profile was unchanged but glucose tolerance increased in hypoxemic mice. Conclusion: Sustained intermittent hypoxemia, per se, modify Ad oligomerization state as well as AdipoR protein abundance in a tissue-specific way. That suggests alteration in Ad-dependant pathways in pathological conditions associated to SIH. Investigation of Ad-pathway components could therefore constitute useful complementary criteria for the clustering of patients with hypoxemia-related diseases and management of co-morbidities, as well as to develop new therapeutic strategies.

Interactions of exercise training and high-fat diet on adiponectin forms and muscle receptors in mice.

BACKGROUND: Metabolic syndrome (MetS) is characterized by systemic disturbances that increase cardiovascular risk. Adiponectin (Ad) exhibits a cardioprotective function because of its anti-inflammatory and anti-atherosclerotic properties. In the bloodstream, this adipocytokine circulates on multimers (Admer), among which high molecular weight (HMW) are the most active forms. Because alterations of Ad plasmatic levels, Admer distribution and receptor (AdipoR) expression have been described in murine models and obese patients, strategies that aim to enhance Ad production or its effect on target tissues are the subject of intense investigations. While exercise training is well known to be beneficial for reducing cardiovascular risk, the contribution of Ad is still controversial. Our aim was to evaluate the effect of exercise training on Ad production, Admer distribution and AdipoR muscle expression in a murine model of MetS. METHODS: At 6 weeks of age, mice were submitted to a standard (SF) or high-fat high-sugar (HF) diet for 10 weeks. After 2 weeks, the SF- and HF-fed animals were randomly assigned to a training program (SFT, HFT) or not (SFC, HFC). The trained groups were submitted to sessions of running on a treadmill 5 days a week. RESULTS AND CONCLUSIONS: The HF mice presented the key problems associated with MetS (increased caloric intake, body weight, glycemia and fat mass), a change in Admer distribution in favor of the less-active forms and increased AdipoR2 expression in muscle. In contrast, exercise training reversed some of the adverse effects of a HF diet (increased glucose tolerance, better caloric intake control) without any modifications in Ad production and Admer distribution. However, increased AdipoR1 muscle expression was observed in trained mice, but this effect was hampered by HF diet. These data corroborate a recent hypothesis suggesting a functional divergence between AdipoR1 and AdipoR2, with AdipoR1 having the predominant protective action on metabolic function.