Dysregulated adipokine secretory profile is associated with endothelial dysfunction in human obesity

Abstract

Abstract Adipokines have been postulated as the potential mediators of the relationship between excess adiposity and vascular dysfunction. In obese patients, vascular dysfunction, characterized by impaired vasodilator responsiveness and/or increased endothelin (ET)-1-dependent vasoconstriction, is, in turn, a predominant abnormality in the atherogenic process. We hypothesized, therefore, that in human obesity vascular dysfunction could be associated with changes in circulating concentrations of adipokines. To test this hypothesis, we compared plasma levels of a panel of adipokines (Luminex assay) in lean subjects (n=42) and obese patients (n=134), and tested their relationship with the forearm flow response (strain-gauge plethysmography) to intra-arterial infusion of endothelium-dependent (acetylcholine; ACh) and -independent (sodium nitroprusside; SNP) vasodilators or ETA receptor antagonism (BQ-123, 10 nmol/min). Compared to lean subjects (n=42), obese patients (n=134) had higher plasma levels of chemerin (4.0±0.1 vs. 2.9±0.2 ng/ml; P<0.001), adipsin (2.1±0.1 vs. 2.7±0.1 μg/ml; P<0.001), leptin (8.1±0.4 vs. 24.4±1.8 ng/ml; P<0.001), and visfatin (7.4±0.8 vs. 8.3±0.3 ng/ml; P=0.015); by contrast, no group difference was observed in circulating levels of adiponectin (3.3±0.3 vs. 3.3±0.1 μg/ml; P=0.78) and retinol-binding protein 4 (57.5±2.5 vs. 64.0±4.1 μg/ml; P=0.13). The forearm flow responses to both ACh and SNP were significantly lower in obese patients (12.6±0.6 ml/min/dl and 11.7±0.3 ml/min/dl, respectively) than in lean controls (18.8±1.4 ml/min/dl and 15.1±0.7 ml/min/dl, respectively; all P<0.001). The vasodilator response to BQ-123, by contrast, was higher in obese (53.7±4.5% increase from baseline) than in lean subjects (18.5±7.3%; P<0.001). Similarly, plasma insulin levels were higher in obese (14.9±0.8 μU/ml) than in lean subjects (6.8±0.7 μU/ml; P<0.001). At the linear regression analyses, a significant inverse correlation was found between circulating levels of visfatin and the vasodilator response to ACh (R=0.22; P=0.03); no linear association, however, was observed between the response to ACh and the other measured adipokines (all P>0.05); similarly, no correlation was seen between plasma adipokines and the vasodilator response to SNP (all P>0.05). On the other hand, a significant linear relationship was observed between the vasodilation elicited by B-123 and plasma levels of chemerin (R=0.30, P=0.012) and adipsin (R=0.38, P<0.001), but not those of the other adipokines (all P>0.05). In conclusion, circulating concentrations of selected adipokines, such as visfatin, chemerin and adipsin, are variably associated with obesity-related decrease in endothelium-dependent vasodilation and increase in ET-1-dependent vasoconstriction. These findings are consistent with the notion that adipokines may influence vascular dysfunction and make these molecules promising targets for prevention. Funding Acknowledgement Type of funding source: None