Leptin is a key mediator of signals regulating food intake and energy expenditure and exerts potent immunomodulatory effects. We investigated the mechanisms mediating the action of leptin on GH secretion from peripheral blood mononuclear cells (PBMCs). Using immunofluorescence microscopy, we demonstrated a polarized expression pattern of leptin receptor protein on the surface of mononuclear cells and constitutive expression of GH in PBMCs. Leptin exhibited a dose-dependent stimulatory effect on GH secretion by PBMCs and also up-regulated the GH receptor gene expression. We did not observe any additive effects of leptin on GH secretion upon activation of cells with the plant mitogen phytohemagglutinin, unlike leptin, phytohemagglutinin exerted no effect on GH receptor mRNA expression. Leptin led to a nitric oxide (NO) synthase (NOS)-specific, dose-dependent increase in NO production from PBMCs because leptin-induced NO release was blocked by the addition of the NOS inhibitor N^ω-Nitro-l-arginine methyl ester and protein kinase C (PKC) inhibitor calphostin C. This leptin-induced GH secretion was dependent on both PKC and NO activation because the addition of PKC and NOS inhibitors inhibited leptin-induced GH production. Although the addition of sodium nitroprusside, a spontaneous liberator of NO, stimulated GH release from PBMCs, leptin had no additive or synergistic effect on sodium nitroprusside-induced GH production. Together, these findings demonstrate a unique action of leptin on immune cells via its ability to stimulate the GH production by blood mononuclear cells via PKC- and NO-dependent pathways. These data also support a probable role for local immune-derived GH in mediating some of the pleiotropic actions of leptin.