A51 MICROBIALLY-MEDIATED IMPAIRMENT OF VAGAL AFFERENT NEURONAL EXCITABILITY IS OREXIN RECEPTOR DEPENDENT
Notice bibliographique
Résumé
Abstract Background An impairment of vagally-mediated satiety signalling has been implicated in the caloric imbalance that leads to weight gain during obesity. Previous studies have suggested that a reduction in the excitability of vagal afferent neurons with cell bodies in nodose ganglia (NG) was responsible, but the cellular mechanisms are unclear. Host and bacterially derived mediators present in the small intestine and stool provide a physiologically relevant model to help elucidate the role luminal mediators play in modulating vagal afferent neuronal excitability. Aims We hypothesize that the microbiota of obese individuals and mice produce mediators that impair NG neuron excitability and satiety in mice. Methods Perforated patch clamp was used to measure the excitability of NG neurons following exposure to human and mouse fecal supernatants (FS), mouse jejunal supernatants (JS), and mice serum samples. Human FS were from ampersand:003E 5 healthy human donors or FS from ampersand:003E 5 obese donors. Mice FS, JS and serum samples were collected from ampersand:003E 5 obese mice fed a high-fat diet and ampersand:003E 5 control mice fed a normal diet. Results NG neurons incubated in FS from obese participants were significantly less excitable (rheobase was 30% higher and action potential discharge at 2x rheobase was 50% lower) than NG neurons exposed to FS from non-obese participants. NG neurons incubated in FS or JS from obese mice were also significantly less excitable (rheobase was 65% higher and action potential discharge at 2x rheobase was 50% lower) than NG neurons incubated with FS or JS from control mice. Lastly, NG neurons incubated with obese mouse serum were significantly less excitable (rheobase was 50% higher and action potential discharge at 2x rheobase was 80% lower) than NG neurons incubated with serum from control mice. We then attempted to identify mediators that may account for this inhibitory effect by using receptor antagonists that block GABA, ghrelin, and orexin signalling. Ghrelin and GABA receptor antagonists did not block the inhibitory effect of obese patients’ FS on NG neurons but the orexin receptor 1 antagonist (SB-334867;10µM) did. Following this, we incubated the orexin receptor 1 antagonist (SB-334867;10µM) on NG neurons incubated with mouse FS and JS and observed a similar blocking of inhibitory effects back to control values. Conclusions These findings suggest that the gut luminal contents of obese mice and humans contain an orexin receptor agonist that inhibits satiety and may contribute to over-eating. Funding Agencies CIHRNSERC
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».