Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension.
Nitric oxide (NO) plays a major role in the regulation of cardiovascular and metabolic homeostasis, as evidenced by insulin resistance and arterial hypertension in endothelial NO synthase (eNOS) null mice. Extrapolation of these findings to humans is difficult, however, because eNOS gene deficiency has not been reported. eNOS gene polymorphism and impaired NO synthesis, however, have been reported in several cardiovascular disease states and could predispose to insulin resistance. High-fat diet induces insulin resistance and arterial hypertension in normal mice. To test whether partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension during metabolic stress, we examined effects of an 8-week high-fat diet on insulin sensitivity (euglycemic clamp) and arterial pressure in eNOS(+/-) mice. When fed a normal diet, these mice had normal insulin sensitivity and were normotensive. When fed a high-fat diet, however, eNOS(+/-) mice developed exaggerated arterial hypertension and had fasting hyperinsulinemia and a 35% lower insulin-stimulated glucose utilization than control mice. The partial deletion of the eNOS gene does not alter insulin sensitivity or blood pressure in mice. When challenged with nutritional stress, however, partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension, providing further evidence for the importance of this gene in linking metabolic and cardiovascular disease.
Cook
Stéphane
S
Department of Internal Medicine and the Botnar Center for Clinical Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Hugli
Olivier
O
Egli
Marc
M
Ménard
Barbara
B
Thalmann
Sébastien
S
Sartori
Claudio
C
Perrin
Christophe
C
Nicod
Pascal
P
Thorens
Bernard
B
Vollenweider
Peter
P
Scherrer
Urs
U
Burcelin
Rémy
R
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015309:Glucose Clamp Technique; D006339:Heart Rate; D006801:Humans; D006946:Hyperinsulinism; D006973:Hypertension / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D017384:Sequence Deletion / Q000235:genetics*
D001786:Blood Glucose; D004041:Dietary Fats; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse