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Spalt-related is a catabolic switch activated by prolonged starvation

ABSTRACT: Nutrient intake is tightly linked to animal energy metabolism and growth. Inhibition of anabolic processes during nutrient deprivation is a critical stress response necessary for survival. However, how transient vs. prolonged nutrient deprivation is sensed by the key metabolic organs and which downstream pathways mediate metabolic regulation under these conditions remain insufficiently understood. Here we uncover an unexpected role for the transcription factor Spalt-related (Salr), a known to be involved in wing morphogenesis, as a regulator of growth and metabolism upon nutrient starvation. Specifically, we observed that Salr is necessary and sufficient to inhibit cellular and organismal growth as well as lipid storage in the Drosophila fat body. Our results indicate that Salr inhibits anabolic processes through the regulation of mTOR complex 1 activity as well as by directly controlling genes involved in lipid catabolism and autophagy. We discovered that Salr and FoxO, a known downstream target of insulin signalling, act on overlapping set of target genes, but are regulated in a sequential manner. While FoxO is activated transiently upon starvation, Salr displays delayed activation kinetics. In conclusion, our results reveal a novel starvation-activated catabolic switch in the fat body, which is closely interconnected with the insulin/mTOR pathway.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE305957 | GEO | 2026/06/23

REPOSITORIES: GEO

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Project description:Sonntag2012 - mTOR model - IRS dependent regulation of AMPK by insulin TSC1-TSC2 complex has two states: 1) active (TSC1_TSC2_pS1387), regulated by AMPK_pT172; 2) inactive (TSC1_TSC2_pT1462) regulated by Akt_pT308. Particularly, mTORC1 is inhibited by TSC1_TSC2 in active state. AMPK is activated at T172 by the species IRS1_p activated by the insulin receptor upon insulin stimulation. Consequently, AMPK_pT172 is inhibited by mTORC1_pS2448 indirectly by the p70-S6K-negative feedback loop. This model is described in the article: A modelling-experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin. Sonntag AG, Dalle Pezze P, Shanley DP, Thedieck K. FEBS J. 2012 Sep; 279(18): 3314-3328 Abstract: Mammalian target of rapamycin (mTOR) kinase responds to growth factors, nutrients and cellular energy status and is a central controller of cellular growth. mTOR exists in two multiprotein complexes that are embedded into a complex signalling network. Adenosine monophosphate-dependent kinase (AMPK) is activated by energy deprivation and shuts off adenosine 5'-triphosphate (ATP)-consuming anabolic processes, in part via the inactivation of mTORC1. Surprisingly, we observed that AMPK not only responds to energy deprivation but can also be activated by insulin, and is further induced in mTORC1-deficient cells. We have recently modelled the mTOR network, covering both mTOR complexes and their insulin and nutrient inputs. In the present study we extended the network by an AMPK module to generate the to date most comprehensive data-driven dynamic AMPK-mTOR network model. In order to define the intersection via which AMPK is activated by the insulin network, we compared simulations for six different hypothetical model structures to our observed AMPK dynamics. Hypotheses ranking suggested that the most probable intersection between insulin and AMPK was the insulin receptor substrate (IRS) and that the effects of canonical IRS downstream cues on AMPK would be mediated via an mTORC1-driven negative-feedback loop. We tested these predictions experimentally in multiple set-ups, where we inhibited or induced players along the insulin-mTORC1 signalling axis and observed AMPK induction or inhibition. We confirmed the identified model and therefore report a novel connection within the insulin-mTOR-AMPK network: we conclude that AMPK is positively regulated by IRS and can be inhibited via the negative-feedback loop. This model is hosted on BioModels Database and identified by: BIOMD0000000580. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Post-embryonic development of the nematode C. elegans is governed by nutrient availability. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This “L1 arrest” (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. daf-16/FOXO had overlapping but distinct effects on gene expression in L1 arrest compared to daf-2/InsR adults. Notably, dbl-1/TGF-β, a ligand for the Sma/Mab pathway, and daf-36, which encodes an upstream component of the daf-12/NHR steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β and daf-36. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype, and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.

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Spalt-related is a catabolic switch activated by prolonged starvation

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