Leptin induces phosphorylation of neuronal nitric oxide synthase in defined hypothalamic neurons

Endocrinology. 2010 Nov;151(11):5415-27. doi: 10.1210/en.2010-0651. Epub 2010 Sep 29.


Studies have indicated that the neurotransmitter nitric oxide (NO) mediates leptin's effects in the neuroendocrine reproductive axis. However, the neurons involved in these effects and their regulation by leptin is still unknown. We aimed to determine whether NO neurons are direct targets of leptin and by which mechanisms leptin may influence neuronal NO synthase (nNOS) activity. Nicotinamide adenine dinucleotide phosphate diaphorase activity and leptin-induced phosphorylation of signal transducer and activator of transcription-3 immunoreactivity were coexpressed in subsets of neurons of the medial preoptic area, the paraventricular nucleus of the thalamus, the arcuate nucleus (Arc), the dorsomedial nucleus of the hypothalamus (DMH), the posterior hypothalamic area, the ventral premammillary nucleus (PMV), the parabrachial nucleus, and the dorsal motor nucleus of the vagus nerve. Fasting blunted nNOS mRNA expression in the medial preoptic area, Arc, DMH, PMV, and posterior hypothalamic area, and this effect was not restored by acute leptin administration. No difference in the number of neurons expressing nNOS immunoreactivity was noticed comparing hypothalamic sections of fed (wild type and ob/ob), fasted, and fasted leptin-treated mice. However, we found that in states of low leptin levels, as in fasting, or lack of leptin, as in ob/ob mice, the number of neurons expressing the phosphorylated form of nNOS is decreased in the Arc, DMH, and PMV. Notably, acute leptin administration to fasted wild-type mice restored the number of phosphorylated form of nNOS neurons to that observed in fed wild-type mice. Herein we identified the first-order neurons potentially involved in NO-mediated effects of leptin and demonstrate that leptin regulates nNOS activity predominantly through posttranslational mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Fasting / metabolism
  • Female
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Immunohistochemistry
  • In Situ Hybridization
  • Leptin / metabolism*
  • Leptin / pharmacology
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nitric Oxide Synthase Type I / metabolism*
  • Phosphorylation / drug effects*
  • Phosphorylation / physiology


  • Leptin
  • Nitric Oxide Synthase Type I