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Article Dans Une Revue Genetics Année : 2021

Differential Metabolic Sensitivity of Insulin-like-response-and TORC1-Dependent Overgrowth in Drosophila Fat Cells

Résumé

Glycolysis and fatty acid (FA) synthesis directs the production of energy-carrying molecules and building blocks necessary to support cell growth, although the absolute requirement of these metabolic pathways must be deeply investigated. Here, we used Drosophila genetics and focus on the TOR (Target of Rapamycin) signaling network that controls cell growth and homeostasis. In mammals, mTOR (mechanistic-TOR) is present in two distinct complexes, mTORC1 and mTORC2; the former directly responds to amino acids and energy levels, whereas the latter sustains insulin-like-peptide (Ilp) response. The TORC1 and Ilp signaling branches can be independently modulated in most Drosophila tissues. We show that TORC1 and Ilp-dependent overgrowth can operate independently in fat cells and that ubiquitous over-activation of TORC1 or Ilp signaling affects basal metabolism, supporting the use of Drosophila as a powerful model to study the link between growth and metabolism. We show that cell-autonomous restriction of glycolysis or FA synthesis in fat cells retrains overgrowth dependent on Ilp signaling but not TORC1 signaling. Additionally, the mutation of FASN (Fatty acid synthase) results in a drop in TORC1 but not Ilp signaling, whereas, at the cell-autonomous level, this mutation affects none of these signals in fat cells. These findings thus reveal differential metabolic sensitivity of TORC1- and Ilp-dependent growth and suggest that cell-autonomous metabolic defects might elicit local compensatory pathways. Conversely, enzyme knockdown in the whole organism results in animal death. Importantly, our study weakens the use of single inhibitors to fight mTOR-related diseases and strengthens the use of drug combination and selective tissue-targeting.
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hal-03483620 , version 1 (16-12-2021)

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Paternité - Pas d'utilisation commerciale - Pas de modification

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Maelle Devilliers, Damien Garrido, Mickael Poidevin, Thomas Rubin, Arnaud Le Rouzic, et al.. Differential Metabolic Sensitivity of Insulin-like-response-and TORC1-Dependent Overgrowth in Drosophila Fat Cells. Genetics, 2021, 217 (1), pp.iyaa010. ⟨10.1093/genetics/iyaa010⟩. ⟨hal-03483620⟩
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