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 (14)C-catecholamine synthesis from [(14)C] tyrosine, but not from [(14)C] 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 (MAPKs). U0126, an inhibitor of MAPK kinase, abolished the effect of leptin on (14)C-catecholamine synthesis. High concentrations of leptin (10-100 nM) produced an increase in intracellular Ca(2+) concentration, which was blocked by Cd(2+), an inhibitor of voltage-dependent Ca(2+) channels. Concurrent treatment of cells with leptin (10 nM) and acetylcholine (0.3 mM) potently enhanced the stimulatory effect of acetylcholine on (14)C-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 Ca(2+) pathways in the adrenal medulla.
Shibuya
Izumi
I
Departments of Pharmacology and Physiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807-8555, Japan.
Utsunomiya
Kensuke
K
Toyohira
Yumiko
Y
Ueno
Susumu
S
Tsutsui
Masato
M
Cheah
Tat Beng
TB
Ueta
Yoichi
Y
Izumi
Futoshi
F
Yanagihara
Nobuyuki
N
D000313:Adrenal Medulla / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000096:biosynthesis*; D002417:Cattle; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D020738:Leptin / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002070:Butadienes; D002395:Catecholamines; D004791:Enzyme Inhibitors; D020738:Leptin; D009570:Nitriles; C113580:U 0126; D014446:Tyrosine 3-Monooxygenase; D002118:Calcium