The central hypothesis is that vasodilator actions of insulin are already impaired in metabolic syndrome due to loss of dilator and gain of constrictor signals. Cerebral vasodilation to insulin is largely endothelium-dependent. Emerging evidence in animal models suggests insulin resistance disrupts at least six endothelial signaling pathways that could be potential targets, and this proposal focuses on two that most likely reduce CBF in MetSyn: 1) Loss of nitric oxide (NO) vasodilation, and 2) Exaggerated endothelin (ET-1) constriction. These experiments will address three specific aims: