Resting and circadian release of nitric oxide is controlled by leptin in male rats

Because leptin stimulates nitric oxide (NO) release from the hypothalamus and anterior pituitary gland, we hypothesized that it also might release NO from adipocytes, the principal source of leptin. Consequently, plasma concentrations of leptin and NO, estimated from its metabolites NO(3) and NO(2) (NO(3)-NO(2)), were measured in adult male rats. There was a linear increase of both leptin and NO(3)-NO(2) with body weight that was associated with a parallel rise in fat mass. These findings indicate that release of leptin and NO is directly related to adipocyte mass. Furthermore, there was a parallelism in circadian rhythm of both substances, with peaks at 0130 h and nadirs at 0730 h. Measurement of both leptin and NO(3)-NO(2) in plasma from individual rats revealed that NO(3)-NO(2) increased linearly with leptin. Incubation of epididymal fat pads with leptin or its i.v. injection in conscious rats increased NO(3)-NO(2) release. The release of NO(3)-NO(2) in vivo and in vitro exceeded that of leptin by many fold, indicating that leptin activates NO synthase. Leptin increased tumor necrosis factor (TNF)-alpha release at a 100-fold lower dose than required for NO release in vitro and in vivo, suggesting that it also may participate in leptin-induced NO release. However, because many molecules of leptin were required to release a molecule of TNF-alpha in vivo and in vitro, we believe that leptin-induced TNF-alpha release is an associated phenomenon not involved in NO production. The results support the hypothesis that adipocytes play a major role in NO release by activating NO synthase in the adipocytes and the adjacent capillary endothelium.