Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis

J Clin Invest. 1999 Oct;104(7):975-82. doi: 10.1172/JCI5867.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / pharmacology
  • Cerebral Ventricles / drug effects
  • Cerebral Ventricles / physiology
  • Diencephalon / drug effects
  • Diencephalon / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Feeding Behavior / drug effects*
  • Hydroxyindoleacetic Acid / metabolism
  • Injections, Intraventricular
  • Leptin / administration & dosage
  • Leptin / pharmacology*
  • Male
  • Mice
  • Mice, Knockout
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / deficiency
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type I
  • Nitroarginine / pharmacology
  • Serotonin / metabolism*
  • Tryptophan / metabolism
  • Weight Gain / drug effects*


  • Enzyme Inhibitors
  • Leptin
  • Nitroarginine
  • Serotonin
  • Hydroxyindoleacetic Acid
  • Tryptophan
  • Arginine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse