High-fat feeding induces hypertension and vascular dysfunction via free fatty acid-mediated impairment of eNOS phosphorylation, rather than defective upstream signaling via Akt.
Does high-fat diet-induced endothelial dysfunction and hypertension result from impaired insulin/Akt signaling or free fatty acid-mediated impairment of eNOS?
High-fat diet-induced vascular dysfunction and hypertension are driven by free fatty acid-mediated impairment of eNOS phosphorylation rather than defective upstream Akt signaling.
Impaired insulin signaling via phosphatidylinositol 3-kinase/Akt to endothelial nitric oxide synthase (eNOS) in the vasculature has been postulated to lead to arterial dysfunction and hypertension in obesity and other insulin resistant states. To investigate this, we compared insulin signaling in the vasculature, endothelial function, and systemic blood pressure in mice fed a high-fat (HF) diet to mice with genetic ablation of insulin receptors in all vascular tissues (TTr-IR(-/-)) or mice with genetic ablation of Akt1 (Akt1-/-). HF mice developed obesity, impaired glucose tolerance, and elevated free fatty acids that was associated with endothelial dysfunction and hypertension. Basal and insulin-mediated phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in the vasculature was preserved, but basal and insulin-stimulated eNOS phosphorylation was abolished in vessels from HF versus lean mice. In contrast, basal vascular eNOS phosphorylation, endothelial function, and blood pressure were normal despite absent insulin-mediated eNOS phosphorylation in TTr-IR(-/-) mice and absent insulin-mediated eNOS phosphorylation via Akt1 in Akt1-/- mice. In cultured endothelial cells, 6 hours of incubation with palmitate attenuated basal and insulin-stimulated eNOS phosphorylation and NO production despite normal activation of extracellular signal-regulated kinase 1/2 and Akt. Moreover, incubation of isolated arteries with palmitate impaired endothelium-dependent but not vascular smooth muscle function. Collectively, these results indicate that lower arterial eNOS phosphorylation, hypertension, and vascular dysfunction following HF feeding do not result from defective upstream signaling via Akt, but from free fatty acid-mediated impairment of eNOS phosphorylation.
Symons et al. (Fri,) conducted a other in Obesity, insulin resistance, and hypertension. High-fat diet and palmitate exposure vs. Lean mice and normal conditions was evaluated on eNOS phosphorylation, endothelial function, and blood pressure. High-fat feeding induces hypertension and vascular dysfunction via free fatty acid-mediated impairment of eNOS phosphorylation, rather than defective upstream signaling via Akt.