OR01-01 Novel Anti-obesity Phytohormone Promotes Cellular Insulin Sensitivity in Hypothalamic Neurons
Notice bibliographique
Résumé
Abstract C.X. Zhang: None. C. Lieu: None. W. He: None. D.D. Belsham: None. Obesity is a global epidemic and is associated with dangerous comorbidities, such as type 2 diabetes mellitus (T2DM). Insulin is sensed by insulin receptor (INSR)-expressing neurons in the hypothalamus, exerts anorexigenic effects to suppress feeding and promote weight loss. In obesity and T2DM, elevated insulin levels induce cellular insulin resistance in hypothalamic neurons, further dysregulating energy homeostasis. Our lab recently discovered that a plant-based phytohormone, compound X (CX), demonstrates in vivo efficacy for weight loss and maintenance. Notably, oral feeding of CX remarkably decreased body weight and food intake in obese CD-1 mice while maintained on a 60% high-fat diet. Moreover, CX-fed mice had lower basal serum insulin levels and improved glucose tolerance, indicating a protective role of CX against obesity-induced insulin resistance. Given the critical interplay between central insulin resistance and obesity, we hypothesized that CX enhances cellular insulin signalling in hypothalamic neurons. A clonal mouse hypothalamic cell line, mHypoE-46, was treated with 100 µM CX or DMSO for 24 hours. The mRNA/protein expression of INSR was measured, and insulin sensitivity was determined upon insulin re-exposure by phosphorylation levels of protein kinase B (AKT) at Ser473. RNA-sequencing was also performed on mHypoE-46 cells after 4 or 16 hours of 100 µM CX treatment to identify pathways altered by CX. We determined that CX robustly increased mRNA and protein expression of INSR and enhanced insulin-indued AKT phosphorylation. Furthermore, CX upregulated the mRNA expression of phosphatidylinositol 3-kinase regulatory subunit 1 (Pik3r1), a downstream mediator of INSR, in CX-treated cells, further demonstrating an enhanced INSR/PI3K/AKT response. Concurrently, we conducted pathway analysis of the RNA-seq data using GSEA and ErimeR. The mammalian target of rapamycin complex 1 (mTORC1) pathway was identified as a top candidate pathway inhibited by CX, which was then validated by assessing the expression and phosphorylation changes of its downstream effectors. The inhibition of mTORC1 is likely responsible for INSR induction by CX, as chronic mTORC1 activation induces cellular insulin resistance. Accordingly, we hypothesize that CX relieves central insulin resistance via modulation of INSR expression and downstream signalling components, such as PI3K and mTORC1. Selective activators and inhibitors of PI3K and mTORC1 will be used to confirm their involvement in CX signalling. Overall, our study delineates the molecular mechanisms involved in the CX-mediated enhancement of insulin signalling and promotion of cellular insulin sensitivity in hypothalamic neuronal models, advancing our knowledge of central insulin resistance and paving the way for future clinical trials of a new T2DM and obesity plant-based therapeutic for humans. Sunday, June 2, 2024
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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 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,001 |
| 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 | 0,001 |
| 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 ».