Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake

Gustavo Provensi, Roberto Coccurello, Hayato Umehara, Leonardo Munari, Giacomo Giacovazzo, Nicoletta Galeotti, Daniele Nosi, Silvana Gaetani, Adele Romano, Anna Moles, Patrizio Blandina, Maria Beatrice Passani

Research output: Contribution to journalArticlepeer-review


Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not knownwhether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine- synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.

Original languageEnglish
Pages (from-to)11527-11532
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
Publication statusPublished - Aug 5 2014


  • Behavioral satiety sequence
  • BSS
  • Histamine receptors
  • Paraventricular hypothalamic nuclei PVN

ASJC Scopus subject areas

  • General


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