Variable dysregulation of circulating lipocalin-2 in different obese phenotypes: Association with vasodilator dysfunction.

BACKGROUND: Obesity is linked with heightened cardiovascular risk, especially when accompanied by metabolic abnormalities. Lipocalin (LCN) 2 and retinol-binding protein (RBP) 4, two members of the lipocalin family, may be upregulated in insulin resistance and atherosclerosis. We analyzed whether changes in circulating LCN2 and RBP4 in obese individuals relate with impaired vasodilator reactivity, an early stage in atherosclerosis. METHODS: Obese individuals (n = 165), without (n = 48) or with (n = 117) metabolic abnormalities, and lean subjects (n = 42) participated in this study. LCN2 and RBP4 were measured by Luminex assay. Endothelium-dependent and -independent vasodilation to acetylcholine and sodium nitroprusside, respectively, was assessed by strain-gauge plethysmography. RESULTS: Circulating LCN2 was higher in obese than in lean subjects (p < 0.001), whereas RBP4 was not different between the two groups (p = 0.12). The vasodilator responses to both acetylcholine and nitroprusside were impaired in obese individuals (p < 0.001 vs lean subjects), with no difference between those with metabolically healthy or unhealthy obesity (p > 0.05). In the whole population, vasodilator responses to acetylcholine (R = 0.23, p = 0.01) and nitroprusside (R = 0.38, p < 0.001) had an inverse, linear relationship with circulating LCN2; no correlation, by contrast, was observed between circulating RBP4 and vasodilator reactivity (both p > 0.05). In a subgroup of obese patients with diabetes (n = 20), treatment with metformin (n = 10) or pioglitazone (n = 10) did not modify circulating LCN2 and RBP4 or vascular reactivity (all p > 0.05). CONCLUSIONS: Circulating LCN2, but not RBP4, is higher in obese than in lean individuals. Interestingly, changes in LCN2 inversely relate to those in vasodilator function, thereby making this protein a potential biomarker for risk stratification in obesity.

Mirabegron relaxes arteries from human visceral adipose tissue through antagonism of α1-adrenergic receptors.

AIM: As inadequate perfusion has emerged as a key determinant of adipose tissue dysfunction in obesity, interest has grown regarding possible pharmacological interventions to prevent this process. Mirabegron has proved to improve insulin sensitivity and glucose homeostasis in obese humans via stimulation of ß3-adrenoceptors which also seem to mediate endothelium-dependent vasodilation in disparate human vascular beds. We characterized, therefore, the vasomotor function of mirabegron in human adipose tissue arteries and the underlying mechanisms. METHODS: Small arteries (116-734 µm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. After vessels had been contracted, changes in vascular tone in response to mirabegron were determined under different conditions. RESULTS: Mirabegron did not elicit vasorelaxation in vessels contracted with U46619 or high-K+ (both P > 0.05). Notably, mirabegron markedly blunted the contractile effect of the α1-adrenergic receptor agonist phenylephrine (P < 0.001) either in presence or absence of the vascular endothelium. The anti-contractile action of mirabegron on phenylephrine-induced vasoconstriction was not influenced by the presence of the selective ß3-adrenoceptor blocker L-748,337 (P < 0.05); lack of involvement of ß3-adrenoceptors was further supported by absent vascular staining for them at immunohistochemistry. CONCLUSIONS: Mirabegron induces endothelium-independent vasorelaxation in arteries from visceral adipose tissue, likely through antagonism of α1-adrenoceptors.

Variable Changes of Circulating ANGPTL3 and ANGPTL4 in Different Obese Phenotypes: Relationship with Vasodilator Dysfunction.

Obesity associates with premature atherosclerosis and an increased burden of cardiovascular disease, especially when accompanied by abnormalities of lipid and glucose metabolism. Angiopoietin-like (ANGPTL)3 and ANGPTL4 are metabolic regulators, whose upregulation is associated with dyslipidemia, insulin resistance and atherosclerosis. We analyzed, therefore, changes in circulating ANGPTL3 and ANGPTL4 in obese patients with different metabolic phenotypes and their relation with impaired vasodilator reactivity, an early abnormality in atherosclerosis. Compared to the lean subjects (n = 42), circulating ANGPTL3 was elevated (both p > 0.001) in the patients with metabolically unhealthy obesity (MUO; n = 87) and type 2 diabetes (T2D; n = 31), but not in those with metabolically healthy obesity (MHO; n = 48, p > 0.05). Circulating ANGPTL4, by contrast, was increased in all obese subgroups (all p < 0.001 vs. lean subjects). Vasodilator responses to both acetylcholine and sodium nitroprusside were reduced in the three obese subgroups vs. lean subjects (all p < 0.001), with greater impairment in the patients with T2D than in those with MHO and MUO (all p < 0.05). In the whole population, an inverse relationship (r = 0.27; p = 0.003) was observed between circulating ANGPTL4 and endothelium-dependent vasorelaxation. Circulating ANGPTL3 and ANGPTL4 undergo variable changes in obese patients with different metabolic phenotypes; changes in ANGPTL4 relate to endothelial dysfunction, making this protein a possible target for vascular prevention in these patients.

Mechanisms of SGLT2 (Sodium-Glucose Transporter Type 2) Inhibition-Induced Relaxation in Arteries From Human Visceral Adipose Tissue.

As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116-734 µm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals (P=0.02). The vasorelaxing response to canagliflozin was not modified (P=0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by H2O2 scavenging (catalase); also, canagliflozin-induced relaxation was similar (P=0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na+/H+ exchanger 1 inhibitor BIX (P=0.67), but greater than that to the Na+/Ca++ exchanger inhibitor SEA 0400 (P=0.001), hinting a role of Na+/H+ exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide (P=0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.