Volatile food signal activates DHAP shunt to elicit protective fmo-2 response in C. elegans

Animals must regulate gene expression to maintain homeostasis in fluctuating environments. C. elegans navigate unreliable bacterial food patches using bacterially produced volatiles to guide foraging behavior. Whether these olfactory cues also trigger anticipatory metabolic responses at the transcriptional level remains unknown. Using a high-resolution transcriptomic time-course analysis, we discover that exposure to the bacterial volatile diacetyl induces transient expression of enzymes in the DHAP shunt, a metabolic pathway at the intersection of glycolysis and lipid biosynthesis. This pathway is also upregulated during hyperosmotic and glucotoxic stress, while normally suppressed during food deprivation. We demonstrate that activating the DHAP shunt via food cue or hyperosmotic shock enhances an fmo-2-dependent starvation response, resulting in increased thermotolerance. We identify the conserved transcription factors MDT-15 and NHR-49 as DHAP shunt regulators across these distinct stress types. Our findings reveal that C. elegans employ an olfactory food cue to pre-emptively activate nutritional stress responses at the transcriptional level, linking sensory perception to metabolic adaptation. More broadly, we identify the conserved DHAP shunt as a manipulable node that integrates multiple stress inputs and could be targeted to harness the health benefits associated with food deprivation.