Dietary obesity in the rat induces endothelial dysfunction without causing insulin resistance: a possible role for triacylglycerols.
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.
Naderali
E K
EK
Diabetes and Endocrinology Research Unit, Department of Medicine, University of Liverpool, UCD, Daulby Street, Liverpool L69 3GA, UK. naderali@liverpool.ac.uk
Brown
M J
MJ
Pickavance
L C
LC
Wilding
J P
JP
Doyle
P J
PJ
Williams
G
G
D000704:Analysis of Variance; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000097:blood; D016014:Linear Models; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D009213:Myography; D009765:Obesity / Q000097:blood / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D014280:Triglycerides / Q000097:blood / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D005230:Fatty Acids, Nonesterified; D020738:Leptin; D014280:Triglycerides; D014665:Vasodilator Agents