Prohibitin – At the crossroads of obesity-linked diabetes and cancer
Notice bibliographique
Résumé
The promoter of a gene that is selectively expressed in just a few cell types provides unique opportunities to study: (1) the pleiotropic function of a protein in two different cell types including the cell compartment specific function, and (2) the crosstalk between two cell/tissue types at the systemic level. This is not possible with a ubiquitous or a highly specific gene promoter. The adipocyte protein-2 ( aP2) is one such gene. It is primarily expressed in adipocytes, but also selectively in monocytic macrophages and dendritic cells, among various immune cell types. Thus, the adipocyte protein-2 gene promoter provides an opportunity to simultaneously manipulate adipose and immune functions in a transgenic animal. Prohibitin (PHB) is a pleiotropic protein that has roles in both adipocytes and immune cells. Adipocyte specific functions of prohibitin are mediated through its mitochondrial function, whereas its immune functions are mediated in a phosphorylation-dependent manner. We capitalized on this attribute of prohibitin to explore the crosstalk between adipose and immune functions, and to discern mitochondrial and plasma membrane-associated cell signaling functions of prohibitin, by expressing wild type prohibitin (Mito-Ob) and a phospho-mutant form of prohibitin (m-Mito-Ob) from the protein-2 gene promoter, individually. Both transgenic mice develop obesity in a sex-neutral manner, but develop obesity-related metabolic dysregulation in a male sex-specific manner. Subsequently, the male Mito-Ob mice spontaneously developed type 2 diabetes and liver cancer, whereas the male m-Mito-Ob mice developed lymph node tumors or autoimmune diabetes in a context-dependent manner. This review provides a point of view on the role of prohibitin in mediating sex differences in adipose and immune functions at the systemic level. We discuss the unique attributes of prohibitin and provide a new paradigm in adipose-immune crosstalk mediated through a pleiotropic protein. Impact statement Prohibitin (PHB) is ubiquitously expressed and plays a role in adipocyte-immune cell cross-talk. Both male and female transgenic mice expressing wild-type PHB in adipose tissue and in macrophages are obese, but only males develop diabetes and liver cancer. When the mice express PHB mutated on tyrosine-114 in adipocytes and macrophages, both males and females are still obese, but none develops liver cancer; instead, males develop lymph node tumors. Adipocyte specific functions of PHB are mediated through its mitochondrial function, whereas its immune functions are mediated in a phosphorylation-dependent manner. Thus, PHB appears to be an important molecule linking obesity, diabetes, and cancer. In addition, this link appears to be affected by sex steroids. Therefore, targeting PHB may lead to a better understanding of the pathogenesis of obesity, diabetes and cancer.
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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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,002 |
| 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 ».