A267 ROLE OF INTESTINAL EPITHELIAL NUCLEAR RECEPTOR HNF4A DURING METABOLIC DISORDERS
Notice bibliographique
Résumé
Abstract Background HNF4α belongs to the hormone nuclear receptor family and is expressed in liver, intestinal epithelium and pancreas where it regulates genes involved in the control of metabolism. Inactivating mutations in the HNF4A gene cause several forms of maturity-onset diabetes of the young (MODY). However, the specific deletion of Hnf4a in mouse pancreatic beta cells does not lead to diabetes, suggesting the contribution of other tissues, such as the intestine, are necessary for the progression of the disease. Aims Our main hypothesis was that intestinal epithelial HNF4α regulates gene products that act through a paracrine mode of communication in the context of glucose metabolism. The aims of this study were to investigate the impact of deleting Hnf4a in the mouse intestinal epithelium during glucose homeostasis and to identify molecular mechanisms involved during glucose-induced obesity resistance. Methods The Villin-Cre recombinase transgenic mouse model was used to conditionally delete Hnf4a in the intestinal epithelium (Hnf4adeltaIEC). Hnf4adeltaIEC mice were put on a high sugar diet for 8 to 12 weeks, using a 30% sucrose supplemented ab lithium water. Blood glucose values in controls and mutants were measured from whole venous blood from fasted mice or during glucose and insulin tolerance tests. Mouse serum hormone levels (Ghrelin, Fibroblast-growth factor-15 (Fgf15), Insulin, Cholecystokinin (CCK), etc.) were measured using mouse ELISA kits. The Promethion High-Definition Room Calorimetry System was used for indirect calorimetry and metabolic studies. Results Both male and female Hnf4adeltaIEC mice displayed a metabolic resistance to develop obesity under sucrose supplementation when compared to control mice. While male mutant mice showed a resistance to obesity after only 2 weeks of treatment, female mutant mice took at least 6 weeks to display some resistance. The gut hormones ghrelin and Fgf15 were also found modified in fasted mutant mice. Female mutant mice presented a significant increase of 1.8 fold in circulating Fgf15 and an increase of 1.4 fold in circulating ghrelin. Similar changes were observed in male mutant mice. However, only male mutant mice presented an insulin resistance and an oral glucose tolerance after between 6 and 8 weeks. Brown adipose tissue (BAT) whitening was observed after 8 weeks of sucrose treatment in control obese animals, a condition that was prevented in Hnf4adeltaIEC mice. Conclusions The identification of paracrine intestinal targets for HNF4α in association with glucose metabolism will provide a better understanding of the molecular nature of tissues crosstalk in energy balance and in metabolism disorders including diabetes and obesity. Funding Agencies CIHR
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| 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 | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 source (Gemma direct ou Codex distillé), 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 ».