Adaptation to nutritional changes is a prominent example of plasticity in living organisms. Evolutionary conserved pathways like Insulin signaling, mechanistic Target of Rapamycin (mTOR), TGF- beta , caloric restriction (CR) and Notch receptor pathways have been characterized for their effects in growth and reproduction along with changes in fat metabolism in response to nutritional stress. Within each of these pathways "canonical" transcription factors (TFs) control the expression of distinctive downstream effectors. On the other hand, many TFs have shared regulators and targets. Given the plasticity in nutrient responses, it is an open question whether different upstream nutrient sensors would canalize nutritional information through their canonical TFs to activate adaptive responses, or whether the adaptive downstream effectors would be controlled by a small subset of specialized TFs common to all nutrient sensing pathways modulating a given adaptive molecular response. We have performed transcriptional analyses to dissect the regulation of genes encoding the C. elegans lysosomal lipases
lipl-1,
lipl-3 and
lipl-4. Although known to have at least partially redundant roles, here we show that the genes encoding these lysosomal lipases are differentially controlled by a network of transcriptional activators and repressors that yield distinct expression patterns in animals with altered nutrient sensing or nutritional status. Surprisingly, HLH-30 (mammalian TFEB), a transcription factor we established to be required for activation of the lipl genes in fasting conditions, is found to be required for induction of lysosomal lipase upon mTOR inhibition but not in CR, insulin deficient, TGF-beta deficient, sterile worms, or other tested models of metabolic dysregulation. By contrast, DAF-16 (mammalian FOXO) is found to control lysosomal lipases downstream of multiple nutrient sensing pathways. Similarly surprising, PHA-4, a gene activating gene expression in CR animals, and NHR-49 a master activator of beta-oxidation upon fasting, act as repressors of the lipl genes, suggesting a dual role for PHA-4 and NHR-49 in adaptation to food scarcity. Additionally, DAF-3 (co-SMAD), NHR-80 (HNF4), SKN-1 (Nfr2), and HSF-1 contribute to regulation of the expression of the lysosomal lipases. All in all, we found that although the specificity of lipase expression depended on the same TFs downstream of multiple nutrient regulatory pathways, they are also under the promiscuous regulation of disparate TFs. *Way A. and Mony V.K. contributed equally to the work presented in the abstract.