Partial Gene Deletion of Endothelial Nitric Oxide Synthase Predisposes to Exaggerated High-Fat Diet—Induced Insulin Resistance and Arterial Hypertension

Abstract

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.

Central Insulin Regulates Heart Rate and Arterial Blood Flow

“…For example, in skeletal muscle tissue, the endothelial form of NO synthase (eNOS) plays an important role in the intrinsic regulation of insulin-stimulated glucose uptake in vitro and in the regulation of blood flow and substrate delivery during hyperinsulinemic clamp studies in vivo (3). In line with this concept, we and others have shown that in mice, the ablation of the eNOS gene leads to hypertension and insulin resistance (3)(4)(5)(6) and that insulin-regulated eNOS expression is an important feature of diabetes (5,6).…”

The effect of the postnatal environment on altered fetal programming of adult vascular function in mice that lack endothelial nitric oxide synthase

“…Therefore, investigation into whether certain maternal behaviors or components of breast milk are responsible is warranted. The potential modulating role of postnatal nutrition in our model is supported by the findings of Cook et al 17 These investigators found that NOS3 +/− mice fed a normal diet had normal insulin sensitivity and were normotensive. However, when fed a high-fat diet over an 8-week period, they developed exaggerated arterial hypertension and had fasting hyperinsulinemia and a 35% lower insulinstimulated glucose utilization than control mice.…”

Uric acid transport and disease

“…NO, described initially as an endothelial cell-derived relaxing factor, is an important regulatory molecule in the cardiovascular system, and reduced NO levels are associated with hypertension and insulin resistance (35)(36)(37). Urate can react directly with NO under aerobic conditions to generate an unstable nitrosated uric acid product that can transfer NO to other molecules such as glutathione (ref.…”