Molecular mechanisms of leptin receptor signaling in ovarian granulosa cells
Notice bibliographique
Résumé
Extreme deviations from what is considered normal body weight, from anorexia to obesity, have been linked to reduced reproductive function in females. Discovered in 1994, leptin is a signaling hormone released from adipose tissue to mediate satiety effects in the hypothalamus. Leptin secretion is directly proportional to amount of body fat and evidence has accumulated that leptin and its receptor (Lepr) are found in a variety of tissues including granulosa cells (GCs) of the ovary. Thus, leptin through its receptor may play a role in reproductive function in females. Many studies have examined the effects of Lepr in GCs and the ovary, however the results are contradictory and all have been in vitro. Here we present the first in vivo study to examine the role of Lepr in GCs during follicular development and ovulation. Immature superovulated mice were used in all studies and GCs collected by follicle puncture. We first determined the expression profiles of Lepr isoforms (LeprA, LeprB) during follicular and luteal development along with leptin-related signaling molecules and targets. We also analyzed transcription factors potentially regulating Lepr expression in GCs. To examine the response of GCs to leptin in vivo, leptin hormone was administered at various times of follicular and luteal development. Lastly, we blocked Lepr action using a Lepr antagonist (SMLA) and determined its effects on ovulation. LeprA and LeprB were upregulated at 4h post- human chorionic gonadotropin (hCG) with LeprA being the most abundant isoform showing a 23-fold increase from 0 to 4h post-hCG. Leptin was upregulated at the same time and Lepr signaling molecules: signal transducer and activator of transcription 3 (Stat3), and suppressor of cytokine signaling 3 (Socs3), were upregulated just after Lepr induction at 7 and 12h post-hCG, respectively. CCAAT/enhancer-binding protein beta (Cebpb), which was induced at 1h post-hCG, was shown to associate with the Lepr promoter and thus regulate Lepr expression. Early growth response protein 1 (Egr1) protein and mRNA data revealed it to be another potential regulatory transcription factor with upregulation at 1h post-hCG, just prior to Lepr upregulation. Thus, the mRNA profiles of genes examined provide evidence of a role for Lepr during the periovulatory period. This was further confirmed as the in vivo response of GCs to a physiological dose of leptin was enhanced at 6h post-hCG evidenced by phosphorylation of mitogen-activated protein kinase (Mapk) and Stat3 proteins; however showed no change during the early follicular or luteal periods. Leptin treatment also increased expression of ovulation genes: a disintegrin and metalloproteinase with thrombospondin motifs 1 (Adamts1), programmed cell death 1 (Pdcd1), and Egr1. Antagonizing Lepr action reduced ovulation rate by 60% in SMLA-treated animals. This reduction appeared, at least in part, to be due to deregulated gene expression of Adamts10, Adamts19, Hyaluronan synthase 2 (Has2), amphiregulin (Areg), Pentraxin-related protein (Ptx3), and Forkhead box protein O1 (Foxo1). Overall, the results of this study provide molecular mechanisms for Lepr induction and signaling in GCs. In addition, it provides evidence that leptin and Lepr play a positive role during ovulation and are thus essential for optimal female fertility.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».