Regulation of catecholamine synthesis by leptin

Obesity is often associated with cardiovascular and metabolic disorders such as hypertension and hyperglycemia. Leptin, a protein product of the obese gene, regulates satiety and energy expenditure through its receptors in the hypothalamus. Recent studies have shown that leptin has extrahypothalamic and peripheral actions. The presence of leptin receptors has been reported in the adrenal medulla. In the present study, we examined the effects of leptin on catecholamine synthesis in cultured bovine adrenal medullary cells. Leptin (3-30 nM) caused a significant increase in C-14-catecholamine synthesis from [C-14] tyrosine, but not from [C-14] DOPA. Incubation of cells with leptin resulted in an activation and phosphorylation of tyrosine hydroxylase. Leptin caused a transient activation of mitogen-activated protein kinases (MAPK(s). U0126, an inhibitor of MAPK kinase, abolished the effect of leptin on C-14-catecholamine synthesis. High concentrations of leptin (10-100 nM) produced an increase in intracellular Ca2+ concentration, which was blocked by Cd2+ an inhibitor of voltage-dependent Ca2+ channels. Concurrent treatment of cells with leptin (10 nM) and acetylcholine (0.3 mM) potently enhanced the stimulatory effect of acetylcholine on 14C-catecholamine synthesis. Leptin, however, failed to enhance the stimulatory effect of acetylcholine on the phosphorylation and activity of tyrosine hydroxylase. Acetylcholine (0.3 mM) decreased the intracellular pH (pHi). Leptin (10 nM) affected neither the basal pHi nor the acetylcholine-induced fall in pHi. These findings suggest that leptin phosphorylates and activates tyrosine hydroxylase and subsequently stimulates catecholamine synthesis through MAPK and probably Ca2+ pathways in the adrenal medulla.