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Mécanismes moléculaires et cellulaires des processus de différenciation et de plasticité cellulaire pour la formation des adipocytes

Abstract : Adipocytes are the functional units of adipose tissue (AT). Within white AT, white adipocytes contribute to both storage and release of energy within the organism, mainly in the form of fatty acids1. On the other hand, brown adipocytes, from brown AT, have a high capacity to consume fatty acids. This results from the activity of the UnCoupling Protein 1 (UCP1)2. Finally, UCP1+ adipocytes have been described in white AT, notably in response to cold exposure3. These adipocytes are named beige adipocytes and are generated through two pathways: on one hand via adipogenesis from adipose-derived mesenchymal stem/stromal cells (ASC), and on the other hand by conversion of white-to-beige adipocytes4. Being a reversible process, beige conversion highlights the plasticity of these cells. The aim of the thesis was to characterize the molecular mechanisms involved in both processes, by using culture models of human ASC and in vivo mice models. Given the perivascular and pericyte localization of ASC in vivo5,6, we investigated the use of Endothelial Growth Medium 2 (EGM2) for their in vitro expansion as an alternative to Standard culture conditions (Eagle's medium supplemented with fetal calf serum). Our results showed that the TGFß1 contained in serum of culture medium altered the relative immature state of ASC. Indeed, TGFß1 induces their commitment toward osteoblastic, chondroblastic or vascular smooth muscle lineage. Also, the small amount of serum in EGM2 medium, and thus low TGFß1 concentration, preserves ASC immaturity in culture, as well as their strong capacities to differentiate into adipocytes, including beige phenotype. We showed that ASC with high potential to generate beige adipocytes over-expressed SOX2 protein. Our results also showed that expression of SOX2 was positively correlated to both formation of beige adipocytes and to brown adipocytes activation in vivo in cold-exposed mice. In addition, using two types of human ASC models in vitro, we observed that SOX2 was overexpressed during adipogenesis, and even more when cells were differentiated into beige adipocytes. Thus, SOX2 appears to be a key factor involved in AT browning potential and adipocyte plasticity in vivo and in vitro. This thesis has allowed the access to a better understanding of the impact of culture conditions on the biology of ASC and highlighted molecules involved in the plasticity of adipocytes.
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Hélène Leménager. Mécanismes moléculaires et cellulaires des processus de différenciation et de plasticité cellulaire pour la formation des adipocytes. Physiologie [q-bio.TO]. Université Paul Sabatier - Toulouse III, 2019. Français. ⟨NNT : 2019TOU30227⟩. ⟨tel-02936364⟩

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