Abstract 043: Endothelial Adenosine Kinase Deficiency Ameliorates Diet-induced Insulin Resistance

Abstract

Background: Obesity is associated with endothelial dysfunction characterized by reduced bioavailability of nitric oxide (NO). It is well known that adenosine regulates endothelial nitric oxide release and vasodilation. However, it is unclear whether intracellular adenosine is able to modulate endothelial nitric oxide production and diet-induced metabolic disorders. This study is to investigate the effect of elevated intracellular adenosine caused by adenosine kinase (ADK) deletion or knockdown on endothelial nitric oxide production and diet-induced insulin resistance as well as the pathways associated to this effect. Methods and results: Endothelial-specific ADK knockout mice fed a high-fat diet show decreased fasting blood glucose and insulin, suppressed adipose tissue inflammation and hepatic steatosis, increased skeletal muscle arteriole vasodilation in an eNOS dependent manner. Mechanistically, ADK knockdown in Human Umbilical Vein Endothelial Cells (HUVECs) with adenoviral ADK shRNA elevated both intracellular and extracellular adenosine, and consequently increased endothelial nitric oxide synthase (eNOS) expression and activation, resulting in an increase in NO production, insulin uptake and vasodilatory-stimulated phosphoprotein (VASP) phosphorylation. Treatment of HUVECs with adenosine A2b receptor antagonist MRS 1754 abolished ADK-knockdown induced eNOS expression. eNOS phosphorylation in ADK-knockdown HUVECs were not interfered with adenosine receptors antagonists. Conclusion: ADK knockdown-mediated elevation of intracellular adenosine in endothelial cells ameliorates diet-induced insulin resistance and metabolic disorders. This is attributed to an enhancement of NO production caused by increased eNOS activation and expression, the latter is regulated via endothelial adenosine A2b receptor.