Differential Metabolic Sensitivity of Insulin-like-response- and mTORC1-Dependent Overgrowth in Drosophila Fat Cells

The glycolytic/lipogenic axis promotes the synthesis of energetic molecules and building blocks necessary to support cell growth, although the absolute requirement of this metabolic axis must be deeply investigated. Here, we used Drosophila genetics and focus on the mTOR signaling network that controls cell growth and homeostasis. mTOR is present in two distinct complexes, mTORC1 and mTORC2. The former directly responds to amino acids and energetic levels, whereas the latter is required to sustain the signaling response downstream of insulin-like-peptide (Ilp) stimulation. Either signaling branch can be independently modulated in most Drosophila tissues. We confirm this independency in the fat tissue. We show that ubiquitous over-activation of mTORC1 or Ilp signaling affects carbohydrate and lipid 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 lipogenesis in fat cells impedes overgrowth dependent on Ilp-but not mTORC1-signaling. Additionally, ubiquitous deficiency of lipogenesis (FASN mutants) results in a drop in mTORC1 but not Ilp signaling, whereas, at the cell-autonomous level, lipogenesis deficiency affects none of these signals in fat cells. These findings thus, reveal differential metabolic sensitivity of mTORC1- and Ilp-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.