Dietary obesity in the rat induces endothelial dysfunction without causing insulin resistance: a possible role for...

Impaired arterial vasorelaxation, due primarily to endothelial dysfunction, is associated with obesity. To clarify the relationship with insulin resistance and other metabolic disturbances, we studied endothelial-dependent and -independent vascular responses in rats with dietary-induced obesity. Dietary-obese rats had significantly higher body weights (10-32%; P<0.001) and fat-pad masses (220-280%; P<0.001) than lean controls, together with raised plasma levels of triacylglycerols (15-80%; P<0.001), non-esterified fatty acids (13-38%; P<0.05) and leptin (85-180%; P<0.001). However, measures of insulin sensitivity (including the hyperinsulinaemic-euglycaemic clamp in a parallel experiment) were comparable with those in controls. Contractions induced in mesenteric arteries by noradrenaline (0.5-8 micromol/l) were comparable in lean and obese groups, but vasorelaxation in noradrenaline-preconstricted arteries was markedly reduced in dietary-obese rats of both sexes. Concentration-response curves to endothelium-dependent vasorelaxants (acetylcholine, A23187 and insulin) showed significant reductions in maximal relaxation (20-95% less than in leans; P<0.001) and significant rightward shifts in EC(40) (concentration giving 40% of maximal response) (P<0.01). Relaxation in response to the direct NO donor, sodium nitroprusside, showed a lesser impairment (12%; P<0.01) in dietary-obese rats. Maximal relaxation to acetylcholine was correlated inversely in both sexes with fat-pad mass (r(2)=0.37, P<0.05) and plasma triacylglycerols (r(2)=0.51, P<0.01), and with leptin in males only (r(2)=0.35, P<0.05). Independent determinants of acetylcholine-induced relaxation were fat mass and plasma triacylglycerols; plasma insulin and insulin sensitivity had no effect. Dietary-induced obesity severely impaired arterial relaxation in both sexes, particularly at the endothelial level. This is not attributable to insulin resistance, but may be related to moderate hypertriglyceridaemia.