Metabolic rewiring in fat-depleted Drosophila reveals triglyceride:glycogen crosstalk and identifies cDIP as a new regulator of energy metabolism

Tissues store excess nutrients as triglyceride (TG) or glycogen, but how these reserves are sensed and communicate remains poorly understood. Here we identify molecular players orchestrating this metabolic balance, and uncover a signaling molecule that mediates energy homeostasis during fat depletion. We show tissue-specific depletion of fatty acyl-CoA synthase FASN1 in the Drosophila fat body (FB) causes near complete fat loss and metabolic remodeling that dramatically elevates carbohydrate metabolism, leading to a striking [~]20-fold increase in glycogen storage. Proteomics and metabolomics identify key factors necessary for rewiring including glycolysis enzymes and target-of-brain-insulin (tobi). FASN1-deficient flies are viable but starvation sensitive, oxidatively stressed, and infertile. We also identify CG10824/cDIP as upregulated in FASN1-depleted Drosophila. cDIP is a leucine-rich-repeat protein with homology to secreted adipokines that fine-tune energy signaling. We find FB-specific cDIP loss promotes Drosophila adult obesity, and is required for development in the absence of FASN1-dependent lipid storage. Collectively, we show fat-depleted Drosophila rewire their metabolism to complete development, and identify cDIP as a putative new cytokine that signals fat insufficiency and may regulate energy homeostasis.