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| - Brown and beige thermogenic adipose tissues improve energetic homeostasis and represent a potential therapeutic targets for the treatment of obesity and aging associated metabolic diseases. Besides decades of research and the very well-described role of noradrenergic signaling, the mechanisms underlying their plasticity, activation and function are still poorly understood. In contrast to white adipose tissue that stores energy to make it available to the organism, brown adipose tissue dissipates energy as heat, and is involved in non-shivering thermogenesis. This metabolic specificity is permitted by brown adipocytes, which exhibit strong oxidative capacities due to their high content in mitochondria and the expression of the uncoupling protein 1 (UCP1). Beige adipocytes have similar metabolic characteristics but appear in specific regions of certain white adipose tissues by the browning phenomenon, following stimulation such as cold exposure. However, these cells appear in other stress situations, suggesting that they may have other functions than thermogenesis. My team's work has previously shown that lactate and ketone bodies, metabolites produced when substrate fluxes (glucose and fatty acids respectively) exceed oxidative capacities and act as regulators of redox metabolism through inter-cellular and inter-organ dialogues, are powerful inducers of browning. The induction of UCP1 by these metabolites is due to a redox mechanism (increase in NADH,H+/NAD+ ratio), and because UCP1 reduces this redox pressure by accelerating the respiratory chain, browning thus appears as an adaptive mechanism to maintain redox homeostasis. Because the underlying molecular mechanisms were poorly understood, my thesis objective was to characterize the expression of lactate transporters in adipocytes and to understand their role in their plasticity and metabolic activity. The fine mapping of the subcutaneous inguinal adipose tissue in mice, using laser microdissection experiments, gene expression measurement and confocal imaging, revealed i) a strong positive correlation between the expression of the lactate transporter Mct1 (monocarboxylate transporter 1) and that of Ucp1 and (ii) the appearance of UCP1 following cold exposure restricted to the subpopulation of adipocytes expressing MCT1 and pre-existing at thermoneutrality. These results highlight the MCT1 protein as a marker of dormant beige adipocytes, able of be activated during cold exposure. This finding is reinforced by the absence of the MCT1 protein in perigonadic adipose tissue which is resistant to browning, and its strong expression in classical brown adipocytes. While MCT1 is necessary for lactate-induced UCP1 expression, we showed that it was not involved in the Ucp1 regulation by adrenergic signaling. However, lactate oxidation and isotopic profiling experiments showed that MCT1 was essential for the metabolic activity of beige adipocytes, by controlling lactate export and import. Lactate export by MCT1 is necessary for glucose consumption, especially during ß3 adrenergic agonist stimulation, by maintaining the redox NADH,H+/NAD+ ratio which is fundamental for the control of glycolysis. MCT1-dependent lactate import feeds the oxidative metabolism and kreb cycle of these cells. A genetically engineered mouse model showed that inducible MCT1 loss of function in adipocytes impact glycemia during cold exposure, confirming the crucial role of MCT1 and lactate fluxes in the control of glucose metabolism in brown/beige adipose tissues. The proposed mechanisms highlight the fundamental role of MCT1 in beige adipocytes biology and could be extrapolated to brown adipocytes.
- Les tissus adipeux thermogéniques beiges et bruns améliorent l'homéostasie énergétique et représentent des cibles thérapeutiques potentielles pour traiter les maladies métaboliques associées à l’obésité et au vieillissement. Malgré des décennies de recherche et le rôle très bien décrit de la signalisation noradrénergique, les mécanismes sous-jacents à leur plasticité, leur activation et leur fonction restent encore mal compris. Contrairement au tissu adipeux blanc qui stocke l’énergie pour la mettre à disposition de l'organisme, le tissu adipeux brun la dissipe sous forme de chaleur, et participe à la thermogénèse de non frisson. Cette spécificité métabolique est permise par les adipocytes bruns, aux fortes capacités oxydatives dues à leur richesse en mitochondries et à l’expression de la protéine découplante UCP1 (Uncoupling Protein 1). Les adipocytes beiges présentent des caractéristiques métaboliques similaires mais apparaissent dans des zones spécifiques de certains tissus adipeux blancs par le phénomène de brunissement, suite à une stimulation comme l’exposition au froid. Cependant, ces cellules apparaissent dans d’autres conditions de stress, ce qui suggère qu’elles puissent assurer d’autres fonctions que la thermogenèse. Les travaux de mon équipe ont montré que le lactate et les corps cétoniques, des métabolites produits lorsque les flux de substrats (glucose et acides gras respectivement) dépassent les capacités oxydatives et qui agissent comme des régulateurs du métabolisme redox au travers de dialogues inter-cellulaires et inter-tissulaires, sont de puissants inducteurs du brunissement. L’induction d’UCP1 par ces métabolites passe par un mécanisme dépendant du potentiel red/ox (augmentation du ratio NADH,H+/NAD+), et comme UCP1 permet de diminuer ce potentiel red/ox en accélérant le fonctionnement de la chaîne respiratoire, le brunissement apparaît comme un mécanisme adaptatif pour maintenir l’homéostasie red/ox.
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