Differential Metabolic Sensitivity of mTORC1- and mTORC2-Dependent Overgrowth

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.