Role and regulation of microRNAs in adipose tissue during aging
Rôle de la synthèse des miARN par le tissu adipeux dans les pathologies de vieillissement
Résumé
On the one part, dicer, the RNase III endoribonuclease responsible for microRNAs maturation, has been reported to be decreased in adipocytes during ageing. With the use of tamoxifen inducible dicerlox/lox/ adiponectin-CreERT2 mice, we found that adipocyte dicer deficiency promoted the onset of some of the age-related complications such as reduced adipocyte sizes and dysfunctions in systemic metabolism. The abrogation of white adipocyte markers such as Pparγ, Glut4 or Hsl, indicated that dicer is indispensible for the maintainance of white adipocyte identity. In addition, the results that there were lipid accumulation and fibrosis in liver in tamoxifen treated dicerlox/lox/ adiponectin-CreERT2+ mice, indicated that adipocyte dicer deficiency might contribute to liver aging. Mechanistically, mitochondrial function seemed to be upregulated due to adipocyte dicer deficiency, indicated by increased protein levels of OXPHOS components and PGC1α. In line, mitochondria repressors FOXO1 and FOXO3 were phosphorylated and inactivated, whose downstream antioxidant targets Catalase and Sod were also decreased. Moreover, P16, a marker of senescence, exhibited a trend to be increased due to adipocyte dicer deficiency. Since mitochondrial ROS surplus can lead to DNA damage and senescence, we assured that adipocyte dicer deficiency might induce a combination of mitochondrial activation and reduction in detoxification reduction possibly mediated by the inactivation of FOXO1 and FOXO3a. Finally, the result that nutrient restriction positively regulated dicer level in adipocytes further supported that there is a conserved aging pathway in adipocytes involving dicer. On the other part, through microarray screen and RT-qPCR validation, we reported that aging increased mir-1949 in adipocytes in wild type mice and possibly promoted its secretion from perigonadal adipose tissue in vitro. Correspondingly, in vitro results also suggested that senescence increased mir-1949 production and secretion from adipocytes. Functionally, upregulation of mir-1949 in 3T3-F442A adipocytes negatively regulated mitochondrial complex II protein level and oxygen consumption capability, associated with lipid accumulation. Interestingly, sustained upregulation of mir-1949 during adipogenesis of 3T3-F442A preadipocytes, tended to increase white adipocyte markers, such as Leptin, Glut4 or Hsl. Finally, combined with the results that 24h fasting significantly increased mir-1949 in perigonadal adipose tissue as well as that upregulation of mir-1949 exhibited a trend to increase lipid accumulation in senescent 3T3-F442A adipocytes, we assured that aging increases mir-1949 expression in adipocytes which might try to rescue age-related dysfunctions in adipocytes, such as impaired lipid storage. Nevertheless, the precise actions of mir-1949 need to be validated in vivo by injection of AAV-aP2-mir-1949 mimic into aged mice.
Au cours du vieillissement, le tissu adipeux devient sénescent ce qui conduit à une altération des capacités fonctionnelles de l'adipocyte. En effet, la senescence est un arrêt du cycle cellulaire qui entraîne la perte de fonction et entretient un profil inflammatoire. Ces changements participent à l'installation progressive de pathologies associées au vieillissement comme le diabète, l'athérosclérose ou les maladies neurodégénératives. Afin de mieux comprendre le rôle des sécrétions de l'adipocyte dans la perte de fonction de cette cellule, nous avons analysé la production de micro ARNs de l'adipocyte âgé chez la souris. Depuis plusieurs années, l'étude des micros ARNs montre que ces molécules pourraient devenir des cibles thérapeutiques de premier plan ou des biomarqueurs spécifiques. Dans ce contexte, nous avons analysé et caractérisé le MiRnome de l'adipocyte chez la souris âgée et nous avons pu démontrer que le Mir-1949 pouvait jouer un rôle important dans la perte de fonction de l'adipocyte au cours du vieillissement. En effet, l'expression et la sécrétion adipocytaire de mir- 1949 sont augmentées avec l'âge et semblent être associées à l'état de senescence de la cellule adipeuse. De plus, l'augmentation de mir-1949 provoque une altération des fonctions de l'adipocyte in vitro. L'ensemble de ces résultats préliminaires montre que mir-1949 pourrait devenir une adipokine d'intérêt à cibler au cours du vieillissement.
Domaines
Médecine humaine et pathologie
Origine : Version validée par le jury (STAR)
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