RT Journal Article
SR Electronic
T1 Differential Metabolic Sensitivity of mTORC1- and mTORC2-Dependent Overgrowth
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 606699
DO 10.1101/606699
A1 Maelle Devilliers
A1 Damien Garrido
A1 Mickael Poidevin
A1 Thomas Rubin
A1 Arnaud Le Rouzic
A1 Jacques Montagne
YR 2019
UL http://biorxiv.org/content/early/2019/04/11/606699.abstract
AB The protein kinase mTOR is implicated in metabolic-related diseases and chiefly controls organismal growth and homeostasis in response to nutrients. Activation of mTOR promotes cell growth and enhances a glycolytic/lipogenic axis, suggesting that this metabolic axis is required to sustain mTOR-dependent growth. Here, we used Drosophila genetics to investigate this functional link both at the organismal and cell-autonomous levels. mTOR is present in two distinct complexes mTORC1 and mTORC2, which can be independently modulated in most Drosophila tissues. We confirm this independency in the fat body, the organ that fulfils hepatic and adipose functions. We show that ubiquitous mTOR over-activation affects carbohydrate and lipid metabolism, supporting the use of Drosophila as a powerful model to study the link between mTOR and metabolism. We show that targeted glycolytic or lipogenic restriction in fat body cells exclusively impedes mTORC2-induced overgrowth. Additionally, ubiquitous deficiency of lipogenesis (FASN mutants) results in a drop in mTORC1 but not mTORC2 signaling, whereas, at the cell-autonomous level, lipogenesis deficiency in fat body cells affects neither mTORC1 nor mTORC2 activity. These findings thus, reveal differential metabolic sensitivity of mTORC1- and mTORC2-dependent overgrowth. Furthermore, they suggest that local metabolic defects may elicit compensatory pathways between neighboring cells, whereas 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.AUTHOR SUMMARY Cell growth is essential for animal development but is also deregulated in several human diseases including cancers. The mTOR signaling network controls cell growth in response to nutrients and growth factors. mTOR stimulation has been shown to promote basal metabolism, including the glycolytic/lipogenic axis, which is essential to provide energetic cofactors and building blocks to sustain cell growth. However, the requirement this metabolic axis for mTOR-dependent growth has been poorly investigated yet. To address this issue, we used Drosophila genetics and focused on the fat tissue that fulfils hepatic and adipose functions. Surprisingly, in mosaic animals, where only a few cells were genetically stimulated for mTOR, we observed that metabolic knockdown only moderates cell overgrowth. Additionally, this growth restriction operates for only one of the two mTOR signaling branches, suggesting that mTOR-dependent compensatory processes operate to circumvent metabolic defects. Given that ubiquitous knockdown of this metabolic axis is essential for juvenile development and adult survival, our study reveals that metabolic restriction is unlikely sufficient to counteract overgrowth disorders.