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De la gouttelette lipidique aux adipocytes intramusculaires : vers un lien causal avec l'insulino-résistance ?

Abstract : My PhD research work was focused on the role of muscle lipids in the regulation of energy metabolism and insulin sensitivity. Lipids can be found under two different forms in skeletal muscle: adipocytes located between muscle fibers/bundles and lipid droplets inside muscle fibers (i.e. intramyocellular triacylglycerols or IMTG). These depots, when present in excess, have both been associated with insulin-resistance in humans, mainly because of intracellular lipotoxic lipid accumulation known to impair insulin signaling for IMTG, and through a yet unknown mechanism for adipocytes. First, we isolated and characterized two distinct populations of progenitor cells from human muscle biopsies. The first population is composed of satellite cells (muscle progenitor cells) and display a myogenic differentiation potential in vitro. The second population is composed of cells that acquire the phenotypic and metabolic properties of functional white adipocytes, called fibro/adipogenic progenitors (FAPs). By using these cell models, we showed that FAPs-derived adipocytes secretions are able to impair insulin signaling and action in human skeletal muscle fibers in vitro. This paracrine effect could explain, at least partly, the inverse relationship observed between intramuscular adipocyte content and insulin sensitivity in humans. Secondly, we studied the role of two proteins, G0/G1 Switch Gene 2 (G0S2) and perilipin 5 (PLIN5), in lipid droplets dynamics as well as their impact on lipid metabolism and insulin sensitivity. We showed in vitro that these two proteins play a key role in the control of muscle lipolysis (i.e. IMTG hydrolysis) via the adipose triglyceride lipase (ATGL, catalyzing the limiting step of muscle lipolysis), and that G0S2 and PLIN5 inhibit ATGL activity through direct and indirect mechanisms, respectively. Furthermore, our data showed that G0S2 and PLIN5 invalidation in vivo in mouse skeletal muscle activates lipolysis, increases lipotoxicity and impairs insulin sensitivity. We have also highlighted an important role for PLIN5 in the regulation of fatty acids oxidation, by finely adjusting their availability to energy demand. Overall, these results clearly show on one hand that a crosstalk between adipocytes and fibers within skeletal muscle can lead to an alteration of insulin sensitivity in humans, and on the other hand that G0S2 and PLIN5, two lipid droplet proteins, play a central role in the control of muscle lipid homeostasis and insulin sensitivity. These data help to develop our current understanding of the link between muscle lipids and insulin sensitivity in humans.
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Claire Laurens. De la gouttelette lipidique aux adipocytes intramusculaires : vers un lien causal avec l'insulino-résistance ?. Immunologie. Université Paul Sabatier - Toulouse III, 2016. Français. ⟨NNT : 2016TOU30388⟩. ⟨tel-01899602⟩

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