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

Abstract

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 known whether 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 H 3 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.histamine receptors | behavioral satiety sequence | BSS | paraventricular hypothalamic nuclei | PVN E ating behavior is regulated by central neurotransmitter systems and peripheral stimuli that interact to change the behavioral state and concur to alter homeostatic aspects of appetite and energy expenditure. The fatty acid amide oleoylethanolamide (OEA) is released by the small intestine in a stimulus-dependent manner and suppresses food intake by activating peroxisome proliferator-activated receptor-α (PPAR-α) (1). Systemic administration of OEA induces c-Fos mRNA expression through the vagus nerve to the nucleus of the solitary tract (NST), supraoptic nuclei (SON), and paraventricular hypothalamic nuclei (PVN) and increases the expression of oxytocin (2, 3), which is involved in the central coordination of homeostatic signals and feeding behavior (4). However, it is not known whether OEA recruits other neurotransmitter systems in the brain to reduce food intake. Histaminergic neurons are clustered in the hypothalamic tuberomammillary nuclei (TMN). They send projections organized in functionally distinct circuits impinging on different brain regions (5), and their firing frequency changes according to the behavioral state (6). Brain histamin...

The Endocannabinoid-Like Derivative Oleoylethanolamide at the Gut–Brain Interface: A “Lipid Way” to Control Energy Intake and Body Weight

“…The activation of PVN and SON is paralleled by increased oxytocin mRNA levels, increased peptide neurosecretion, and elevated circulating oxytocin levels [42,53] (Figure 1).In addition, pharmacological blockade of central oxytocin receptors abolishes the hypophagic effects of OEA [42], implying that release of oxytocin in the hypothalamus and/or other brain regions is an obligatory effector of OEA-induced satiety. A noradrenergic pathway from the NST to the hypothalamus seems to mediate OEA effects on feeding behavior and on hypothalamic oxytocin increase, as demonstrated in rats with chemical lesions of hindbrain noradrenergic neurons [122].…”

“…Basically, in nonfood deprived animals, OEA administration increases inter-meal latency (decreasing meal frequency), whereas it decreases also meal size in food deprived animals [42,52]. Recently, it has also been shown that OEA administration induces a clear leftward shifting (an index of early occurrence) in the temporal development of satiety and the premature onset of satiety [53,54].…”

“…Exogenous administration of OEA increases transcription of the early gene c-Fos, a marker of neuronal activation, in the NST [48], it increases c-Fos mRNA and protein expression in oxytocin-immunoreactive neurons in the paraventricular (PVN) and supraoptic nucleus (SON) [42,53] in the histaminergic tuberomammillary nucleus [53] and in the area postrema [121], a circumventricular organ that lacks a functional blood brain barrier (Figure 1). This latter observation suggests a direct action of OEA in the brain stem by reaching the area postrema from the blood stream [42].…”

Intestinal lipid–derived signals that sense dietary fat

“…OEA stimulation of PPARα may act as a "stop" signal for feeding by recruiting afferent sensory fibers, possibly of the vagal nerve (26,28,113). The signal is transferred to the NST in the brainstem, from which neurotransmission continues to magnocellular oxytocin-secreting neurons in the paraventricular (PVN) and supraoptic nucleus (SON) of the hypothalamus (28,116), as well as to histaminergic neurons of the tuberomammillary nucleus (118). ENS, enteric nervous system.…”

“…These findings are consistent with the idea that oxytocin neurotransmission in the CNS plays an obligatory role in the satietyinducing action of OEA (Figure 2). A recent report suggests that central histamine transmission may also be involved (118).…”