Fatty acids and endothelial dysfunction in obesity: role of β-adrenergic stimulated lipolysis

Abstract

Obesity is a risk factor for vascular disease, and endothelial dysfunction is common to both. The mechanism linking obesity and endothelial dysfunction is unclear. Serum free fatty acids (FFAs) are elevated in obesity, and impair endothelium-dependent vasodilation by inducing inflammation and oxidative stress. Elevated FFAs in obesity are partly due to enhanced triglyceride lipolysis, which is increased by sympathetic stimulation of the β-adrenoreceptor. There is evidence of augmented sympathetic activity in obesity. It was hypothesized that β-antagonism would reduce serum FFAs and thereby improve endothelium-dependent vasodilation in fat-fed rats. Further, that β-antagonist-mediated reduction in FFAs would be associated with decreased serum markers of inflammation and oxidation. Male Sprague-Dawley rats (n = 8) were fed a high-fat diet for 16 weeks. During the final 4 weeks, rats received β1 and β3-antagonists (atenolol and SR59230A) by subcutaneous slow-release pellets. Endothelium-dependent vasodilation was assessed in vivo by laser Doppler flowmetry of the femoral artery to measure the flow-time integral (i.e. area under the flow curve) in response to 0.25, 0.75, and 2.5 μg/kg intra-arterial acetylcholine. Markers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)] and oxidative stress [thiobarbituric acid reactive substances (TBARS), arterial nitrotyrosine residues] were also measured. Chronic β1β3-antagonism elevated serum FFAs (p < 0.01) and increased body weight (p < 0.001) in normal and fat-fed rats compared to placebo-pelleted animals. High-fat feeding increased serum triglyceride and leptin concentrations, and this was not increased further by β-antagonist treatment. Antagonist treatment did not change the flow-time integral (p = 0.17). β1β3-antagonism was associated with decreased serum CRP, IL-6 and TNF-α, and increased TBARS. Nitrotyrosine residues were primarily localized to the endothelium, followed by the subendothelium and vascular media. Slot blot analysis of proteins revealed increased nitrosylated protein in both normal and fat-fed animals that received β-antagonist treatment. Increased serum FFAs after chronic β1β3-antagonism was possibly due to attenuation of brown adipose fatty acid oxidation which would prevent uptake of circulating FFAs. Additionally, lipolytic pathways that are independent of β-adrenergic control exist, and may have compensated for attenuated β-mediated lipolysis. Despite elevated FFAs in β1β3-treated rats and known pathologic effects of FFAs on the vascular endothelium, β1β3-antagonist treatment preserved endothelium-dependent vasodilation. This suggests that beneficial effects of β-antagonists on the vasculature are not mediated by FFA-lowering properties. Markers of systemic inflammation were reduced in β1β3-antagonist-treated rats despite increased FFAs. Because FFAs are known to be pro-inflammatory, β-antagonism may preserve endothelium-dependent vasodilation by attenuating FFA-mediated inflammation. In contrast, TBARS and nitrotyrosine were increased with β-antagonism, possibly due to unmitigated FFA-mediated oxidative stress.