Abstract
Concentrations of L‐leucine (physiological isomer) are elevated in the plasma of obese humans as well as both diet‐induced and spontaneously obese rats in association with vascular insulin resistance. Because reduced availability of nitric oxide (NO) has been implicated to play a key role in mediating the metabolic syndrome in obese subjects, this study was conducted to test the hypothesis that elevated levels of L‐leucine may inhibit NO synthesis by endothelial cells (EC). Bovine venular EC were cultured for 48 h in Dulbecco's modified Eagle's medium containing 0.2 mM L‐arginine, 0.5 mM L‐glutamine and 0.1, 0.5 or 2 mM L‐leucine, L‐valine, L‐isoleucine, or D‐leucine. L‐Leucine dose‐dependently increased (P < 0.05) glutamine:fructose aminotransferase (GFAT) activity and the synthesis of glucosamine‐6‐P (a competitive inhibitor of glucose‐6‐P dehydrogenase, an enzyme in the pentose cycle), while inhibiting NO production by EC (P < 0.05). L‐Valine, L‐isoleucine, and D‐leucine had no effect on GFAT activity or NO synthesis in these cells (P >; 0.05). Compared with 0.1 mM L‐leucine, 0.5 and 2 mM L‐leucine reduced pentose cycle activity and intracellular concentrations of NADPH (a cofactor for NO synthase) in a dose‐dependent manner. These results suggest that L‐leucine inhibits NO production by endothelial cells through glucosamine‐mediated reduction of NADPH generation via the pentose cycle. Supported by AHA.
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