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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 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.

SUBMITTER: Provensi G

PROVIDER: S-EPMC4128140 | biostudies-other | 2014 Aug

REPOSITORIES: biostudies-other

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Project description:Spexin (SPX) is a pleiotropic peptide with highly conserved protein sequence from fish to mammals and its biological actions are mediated by GalR2/GalR3 receptors expressed in target tissues. Recently, SPX has been confirmed to be a novel satiety factor in fish species but whether the peptide has a similar function in mammals is still unclear. Using the mouse as a model, the functional role of SPX in feeding control and the mechanisms involved were investigated. After food intake, serum SPX in mice could be up-regulated with elevations of transcript expression and tissue content of SPX in the glandular stomach but not in other tissues examined. As revealed by immunohistochemical staining, food intake also intensified SPX signals in the major cell types forming the gastric glands (including the foveolar cells, parietal cells, and chief cells) within the gastric mucosa of glandular stomach. Furthermore, IP injection of SPX was effective in reducing food intake with parallel attenuation in transcript expression of NPY, AgRP, NPY type 5 receptor (NPY5R), and ghrelin receptor (GHSR) in the hypothalamus, and these inhibitory effects could be blocked by GalR3 but not GalR2 antagonism. In agreement with the central actions of SPX, similar inhibition on feeding and hypothalamic expression of NPY, AgRP, NPY5R, and GHSR could also be noted with ICV injection of SPX. In the same study, in contrast to the drop in NPY5R and GHSR, SPX treatment could induce parallel rises of transcript expression of leptin receptor (LepR) and melanocortin 4 receptor (MC4R) in the hypothalamus. These findings, as a whole, suggest that the role of SPX as a satiety factor is well conserved in the mouse. Apparently, food intake can induce SPX production in glandular stomach and contribute to the postprandial rise of SPX in circulation. Through GalR3 activation, this SPX signal can act within the hypothalamus to trigger feedback inhibition on feeding by differential modulation of feeding regulators (NPY and AgRP) and their receptors (NPY5R, GHSR, LepR, and MC4R) involved in the feeding circuitry within the CNS.

Project description:AimsTo evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate.Materials/methodsThree mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons.ResultsSemaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise.ConclusionsGDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Project description:BackgroundAlthough protein-rich plant foods have recently been touted as an equivalent to animal products, limited data exist regarding the effects of animal vs. plant proteins on appetite, satiety, and subsequent food intake.ObjectiveThe objective was to determine whether a high-protein beef lunch alters the appetitive, hormonal, and neural signals controlling food intake regulation vs. a macronutrient and fiber-matched (MF) or serving size-matched (SS) soy lunch in healthy adults.MethodsA randomized, double-blind, crossover design study was completed in 21 adults (aged 23 ± 1 y; body mass index: 23.8 ± 0.6 kg/m²; mean ± SEM) to compare 400-kcal MF and SS lunches varying in protein quality. The MF lunches contained 24-g beef protein or 24-g soy protein, whereas the SS lunches contained 1 serving of beef (24-g protein/1-g fiber) or soy (14-g protein/5-g fiber). Pre- and postlunch appetite questionnaires and blood sampling were completed over an 8-h period until dinner was voluntarily requested. In addition, pre- and postlunch functional MRI brain scans were completed to assess neural activation in response to food stimuli.ResultsOn average, dinner was requested at ∼250 ± 20 min postlunch with no differences between beef vs. soy within the MF and SS conditions. Furthermore, no differences in hunger, fullness, peptide YY, or glucagon-like peptide-1 responses were observed after the beef vs. soy lunches within the MF and SS conditions. The SS beef meal led to reductions in anterior cingulate activation (-22 ± 6%) vs. soy (+7 ± 9%; P < 0.01) and greater reductions in insular activation (-30 ± 6%) vs. SS soy (-7 ± 10%; P < 0.01). The participants consumed ∼945 ± 78 kcal after the MF meals and 910 ± 74 kcal after the SS meals with no differences between beef vs. soy.ConclusionsWhen comparing 2 high-quality protein sources, such as beef and soy, the type of protein consumed within a mixed meal elicited very little effect on appetite, satiety, and food intake in healthy adults.

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

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