Fatty acids and endothelial dysfunction in obesity: Role of beta-adrenergic stimulated lipolysis

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 (EDV) 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 beta-adrenoreceptor. There is evidence of augmented sympathetic activity in obesity.; It was hypothesized that beta-antagonism would reduce serum FFAs and thereby improve EDV in fat-fed rats. Further, that beta-antagonist-mediated reduction in FFAs would be associated with decreased 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 beta1 and beta 3-antagonists (atenolol and SR59230A) by subcutaneous slow-release pellets. EDV was assessed in vivo by laser Doppler flowmetry of the femoral artery to measure the flow-time integral in response to intra-arterial acetylcholine. Markers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha)] and oxidative stress [thiobarbituric acid reactive substances (TBARS), arterial nitrotyrosine residues] were measured.; beta1beta3-antagonism elevated FFAs (p < 0.01) and increased body weight (p < 0.001) in normal and fat-fed rats. Antagonist treatment did not change the flow-time integral (p = 0.17). beta 1beta3 antagonism was associated with decreased serum CRP, IL-6 and TNF-alpha, and increased TBARS. Nitrotyrosine residues were primarily localized to the endothelium, and slot blot analysis of proteins revealed increased nitrotyrosine in normal and fat-fed animals that received beta-antagonists.; Increased FFAs with beta1beta3-antagonism was possibly due to attenuation of brown adipose fatty acid oxidation preventing uptake of circulating FFAs. Additionally, lipolytic pathways independent of beta-adrenergic control may have compensated for attenuated beta-mediated lipolysis. Despite elevated FFAs and known pathologic effects of FFAs on the endothelium, beta 1beta3-antagonism preserved EDV. This suggests that beneficial effects of beta-antagonists on the vasculature are not mediated by FFA-reducing properties. Inflammatory markers were reduced with beta 1beta3-antagonism despite increased FFAs, suggesting that beta-antagonism may preserve EDV by attenuating FFA-mediated inflammation. Oxidant markers were increased with beta1beta3-antagonism, possibly due to unmitigated FFA-mediated oxidative stress.