Role of microRNAs and of their machinery in the control of brown adipose tissue activity and predisposition to type 2 diabetes
Rôle des microARNs et de leur machinerie dans le contrôle de l'activité du tissu adipeux brun et la prédisposition au diabète de type 2
Résumé
Brown adipose tissue (BAT) has grown over the last ten years into the center of interest for many laboratories due to its capacity to burn energy derived from metabolic substrates into heat. Indeed, in mammals, the development of BAT occurs at the end of gestation to become fully functional at birth. Its thermogenic capacity allows newborns to face extrauterine environment, and thereafter its activity declines with age. This suggests that the intrauterine environment plays an important role in the programming of BAT physiology and metabolism. In a well-known model of intrauterine growth retardation (IUGR), the maternal protein restriction model (called LP for low protein), the young LP progeny is normoglycemic despite an insulin secretion defect but develops insulin resistance and hyperglycemia with age. When I started my thesis work, available results in the laboratory suggested a role of BAT in the dynamic changes of the LP progeny metabolic profile according to the age. Indeed, BAT of young LP rats is hyperactive at 3 months compared to controls while this activity drops back to control levels in old 18-months LP progeny, consistent with the appearance of a type 2 diabetic phenotype. During my thesis, the first objective was to search for the causal role of BAT in the maintenance of glucose homeostasis in young LP progeny. Using a first strategy, we exposed young LP progeny to a cold challenge to activate their BAT. In a second approach, we performed surgical ablation of their BAT. Our results show that young LP progeny is more protected against a cold challenge than controls, due to the high thermogenic capacity of their BAT. However, BAT ablation induces hyperglycemia in young LP animals showing that this tissue is required to maintain their normoglycemia. This work, published in Diabetes in March 2017, suggests that a deleterious fetal environment could reprogram BAT metabolism. The second objective of my thesis was to identify the molecular mechanisms allowing the maintenance of active BAT in young LP progeny. To do so, we compared two models of BAT activation, ie our LP model and a well-known model of BAT activation with an agonist of β-3 adrenergic receptors. In both cases, when BAT is active, we observed a global increase in microRNA (miRNA) expression associated to augmented miRNA machinery expression, and in particular AGO2 expression. Interestingly, when BAT is inactive in old LP animals, miRNA expression and miRNA machinery expression return to control levels. While activation of mature brown adipocytes in vitro leads to an increase in AGO2 protein expression, partial deletion of this protein is sufficient to decrease the thermogenic activity of these cells. Collectively our data suggest that AGO2 and increased miRNA expression contribute to BAT activation. The manuscript concerning this research is in the review process at Molecular Metabolism. In the third part of my PhD research efforts, I have found that in the BAT of young LP progeny several miRNAs are robustly downregulated. We have focused on let-7cp and miR-22-3p, which have the most severe decrease in expression. Our key finding is that these two miRNAs act synergistically to hinder mature brown adipocyte thermogenic activity. This work is in the process of being finalized for publication. In conclusion, during my PhD training I have revealed several novel findings, which lead to a better understanding of BAT physiology and its dysregulation in situations eventuating in perturbed glucose homeostasis. While additional efforts are certainly needed, these contributions advance our vision to leverage BAT as a promising target for the prevention and/or treatment of metabolic perturbations associated to obesity and type 2 diabetes.
Le tissu adipeux brun (TABr) est devenu ces dix dernières années le centre d’intérêt de nombreux laboratoires en raison de sa capacité à dissiper l’énergie apportée par les substrats sous forme de chaleur. Chez les mammifères, le développement du TABr intervient à la fin de la gestation et devient fonctionnel à la naissance. Sa capacité thermogénique permet aux nouveau-nés de s’adapter face à l'environnement extra-utérin, puis son activité régresse avec l’âge. Ceci suggère que l’environnement intra-utérin joue un rôle important dans la programmation de la physiologie et du métabolisme du TABr. Dans un modèle bien décrit de retard de croissance intra-utérin, qu’est la carence protéique maternelle (CP), la jeune progéniture CP est normoglycémique malgré un défaut de sécrétion de l'insuline mais développe avec l'âge une résistance à l'insuline et une hyperglycémie. Lors de mon arrivée au laboratoire, des résultats suggéraient un rôle du TABr dans les changements dynamiques du profil métabolique de la progéniture CP en fonction de l'âge. En effet, le TABr des rats CP est hyperactif à 3 mois par rapport aux animaux contrôles alors qu’il revient au niveau des contrôles chez la progéniture CP âgée de 18 mois, ce qui corrèle avec l’apparition des troubles métaboliques caractéristiques du diabète de type 2. Durant ma thèse, mon premier objectif a été de démontrer le rôle causal du TABr dans le maintien de l’homéostasie glucidique chez les jeunes animaux CP. Pour ce faire, nous avons exposé au froid de jeunes rats CP pour solliciter leur TABr et nous avons procédé à l’ablation chirurgicale de ce tissu. Nos résultats montrent que la jeune progéniture CP est mieux protégée que les contrôles à une exposition au froid grâce à l’activité thermogénique accrue de leur TABr.
Origine : Version validée par le jury (STAR)
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