Impact of Endothelial‐Specific FoxO1 Depletion on the Development of Metabolic Dysfunction in Obesity
Notice bibliographique
Résumé
Background and hypothesis Impaired vascular growth and remodeling is implicated in the disruption of adipose tissue structure and function in obesity, leading to systemic metabolism dysfunction. As Forkhead Box O1 (FoxO1) transcription factor regulates endothelial cell homeostasis and restrains angiogenesis, we investigated the role of endothelial cell FoxO1 in the development of obesity using endothelium FoxO1‐deficient mice. Experimental design To generate endothelial cell‐specific FoxO1 deficient mice (FoxO1 iEC‐D ), conditional FoxO1 L/L floxed mice were bred with mice expressing the tamoxifen‐inducible, Pdgfb promoter‐driven creERT2 recombinase. Cre‐mediated recombination was induced with 5 consecutive intraperitoneal (i.p.) injections of 200 μL of tamoxifen (15 mg/mL) at 4–5 weeks of age. Cre − ;FoxO1 L/L littermates were used as control mice in this study. FoxO1 mRNA levels were analyzed in endothelial cells isolated from epidydimal white adipose tissue (eWAT) by qPCR quantification. To verify the effects of EC‐FoxO1 on diet‐induced obesity, male FoxO1 iEC‐D mice and matched control mice (6–8 weeks‐old, n=10/group) were fed a normal chow (NC, 10.5% fat) or high‐fat (HF) diet (58% fat) for 16 weeks. Results Cre‐mediated recombination resulted in 50% reduction of FoxO1 mRNA levels in endothelial cells of FoxO1 iEC‐D mice. Although food intake of FoxO1 iEC‐D mice consuming a HF diet did not significantly differ from controls through 16 weeks, decreased body weight gain and adiposity were observed in FoxO1 iEC‐D mice at the end of the diet period. In addition, HF FoxO1 iEC‐D mice had lower blood pressure and fasting blood glucose levels, and improved response to i.p. glucose tolerance test but no significant changes in i.p. insulin tolerance test. No significant changes were detected on triglycerides levels in serum, liver, muscle and heart with FoxO1 deletion. Whole‐mount staining and CD31 mRNA analysis indicated increased vascular density in the eWAT of HF FoxO1 iEC‐D mice, which was not associated with significant changes in the mRNA levels of browning markers UCP‐1 and PRDM16. However, gene expression analysis of eWAT showed increased levels of PPARγ and PCG1α and reduced mRNA levels of leptin in HF FoxO1 iEC‐D mice compared with HF control mice. To test if EC‐FoxO1 depletion affects adipose insulin action, ex vivo stimulation of eWAT with insulin was performed and the Akt phosphorylation status was analyzed by Western Blot. While insulin‐stimulated Akt phosphorylation was impaired by HF in control mice, no diet effect was observed in the eWAT from FoxO1 iEC‐D mice, indicating that endothelial‐FoxO1 deletion contributes to maintained insulin sensitivity of adipose tissue. Conclusion Our data suggest that endothelial FoxO1 deletion improves adipose tissue structure and function and these influences may contribute to alleviating systemic metabolic dysfunction in response to high‐fat in mice. Support or Funding Information CIHR
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,000 |
| 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) | 0,000 | 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 ».