This study investigates the vascular actions of adiponectin, a protein secreted by adipose cells that mimics insulin's metabolic actions. The authors hypothesized that adiponectin might stimulate nitric oxide (NO) production in vascular endothelial cells, similar to insulin's action. Using bovine aortic endothelial cells, they found that adiponectin significantly increased NO production by about 3-fold, while lysophosphatidic acid (LPA), a calcium-releasing agonist, increased NO production by about 4-fold. The NO-stimulating effect of adiponectin was blocked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase). Additionally, adiponectin stimulated phosphorylation of Akt at Ser473 and endothelial nitric oxide synthase (eNOS) at Ser1179, which was also blocked by wortmannin. However, the NO-stimulating effect of adiponectin was independent of Akt, as a dominant-inhibitory mutant of Akt did not affect NO production. Instead, the effect was partially dependent on AMP-activated protein kinase (AMPK), as a dominant-inhibitory mutant of AMPK significantly inhibited NO production. These findings suggest that adiponectin stimulates NO production in vascular endothelial cells through PI 3-kinase-dependent pathways involving the phosphorylation of eNOS by AMPK. This novel vascular action of adiponectin may contribute to its metabolic and anti-atherogenic properties.This study investigates the vascular actions of adiponectin, a protein secreted by adipose cells that mimics insulin's metabolic actions. The authors hypothesized that adiponectin might stimulate nitric oxide (NO) production in vascular endothelial cells, similar to insulin's action. Using bovine aortic endothelial cells, they found that adiponectin significantly increased NO production by about 3-fold, while lysophosphatidic acid (LPA), a calcium-releasing agonist, increased NO production by about 4-fold. The NO-stimulating effect of adiponectin was blocked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase). Additionally, adiponectin stimulated phosphorylation of Akt at Ser473 and endothelial nitric oxide synthase (eNOS) at Ser1179, which was also blocked by wortmannin. However, the NO-stimulating effect of adiponectin was independent of Akt, as a dominant-inhibitory mutant of Akt did not affect NO production. Instead, the effect was partially dependent on AMP-activated protein kinase (AMPK), as a dominant-inhibitory mutant of AMPK significantly inhibited NO production. These findings suggest that adiponectin stimulates NO production in vascular endothelial cells through PI 3-kinase-dependent pathways involving the phosphorylation of eNOS by AMPK. This novel vascular action of adiponectin may contribute to its metabolic and anti-atherogenic properties.