Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis.
Leptin administration inhibits diencephalic nitric oxide synthase (NOS) activity and increases brain serotonin (5-HT) metabolism in mice. We evaluated food intake, body-weight gain, diencephalic NOS activity, and diencephalic content of tryptophan (TRP), 5-HT, hydroxyindoleacetic acid (5-HIAA), and 5-HIAA/5-HT ratio after intracerebroventricular (ICV) or intraperitoneal (IP) leptin injection in mice. Five consecutive days of ICV or IP leptin injections induced a significant reduction in neuronal NOS (nNOS) activity, and caused a dose-dependent increase of 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio. Diencephalic 5-HT metabolism showed a significant increase in 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio 3 hours after a single leptin injection. This effect was maintained for 3 hours and had disappeared by 12 hours after injection. After a single IP leptin injection, the peak for 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio was achieved at 6 hours. Single injections of ICV or IP leptin significantly increased diencephalic 5-HT content. Leptin-induced 5-HT increase was antagonized by the coadministration of L-arginine only when the latter was ICV injected, whereas D-arginine did not influence leptin effects on brain 5-HT content. Finally, in nNOS-knockout mice, the appetite-suppressant activity of leptin was strongly reduced, and the leptin-induced increase in brain 5-HT metabolism was completely abolished. Our results indicate that the L-arginine/NO pathway is involved in mediating leptin effects on feeding behavior, and demonstrate that nNOS activity is required for the effects of leptin on brain 5-HT turnover.
Calapai
G
G
Institute of Pharmacology, School of Medicine, I-98124 Messina, Italy.
Corica
F
F
Corsonello
A
A
Sautebin
L
L
Di Rosa
M
M
Campo
G M
GM
Buemi
M
M
Mauro
V N
VN
Caputi
A P
AP
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D004027:Diencephalon / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007276:Injections, Intraventricular; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D019335:Nitroarginine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
D004791:Enzyme Inhibitors; D020738:Leptin; D019335:Nitroarginine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse