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

Volatile food signal activates DHAP shunt to elicit protective fmo-2 response in C. elegans | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Letter Volatile food signal activates DHAP shunt to elicit protective fmo-2 response in C. elegans Martin Denzel, Marco Giorda, Anamitra Sen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8020015/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract 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. Biological sciences/Physiology/Metabolism/Homeostasis Biological sciences/Genetics/Gene expression Full Text Additional Declarations There is NO Competing Interest. Supplementary Files ExtendedDataFigures.pdf Extended data figures Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8020015","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Letter","associatedPublications":[],"authors":[{"id":540481777,"identity":"d4fa75c3-2380-407f-8af2-273163cff95f","order_by":0,"name":"Martin Denzel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYLCCBAYGxgYQ40EFkGBmbiCkgbEBriXhDEgLIxFaYARDYhtcADfQbT/7/MHDHQyy/dLtDx8kzquN5m8HavlRsQ2nFrMz6YYNiWcYjGfOOZBskLjteO6Mw4wNjD1nbuPWciCNsQHonsQNNxKOSSRuO5bbANTCzNiGR8v5ZxAt+28ktv9InHMsdz5BLTdgtkgkszEkNtTkbiCs5RnjjMQ2CeMZN9KYJRKOHcjdCNRyEK9fzqcxfPzZZiPbPyP94YcPNXW5884fPvjgRwVuLVAgAWMcBpMHCKlHBnWkKB4Fo2AUjIIRAgDbRWI6GcTuEgAAAABJRU5ErkJggg==","orcid":"","institution":"Altos Labs","correspondingAuthor":true,"prefix":"","firstName":"Martin","middleName":"","lastName":"Denzel","suffix":""},{"id":540481778,"identity":"20cf6f21-2409-40e9-9e4f-d4ca37278096","order_by":1,"name":"Marco Giorda","email":"","orcid":"","institution":"Altos Labs","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Giorda","suffix":""},{"id":540481779,"identity":"16b50e8c-e277-4f83-81b9-29034867a4ec","order_by":2,"name":"Anamitra Sen","email":"","orcid":"","institution":"Altos Labs","correspondingAuthor":false,"prefix":"","firstName":"Anamitra","middleName":"","lastName":"Sen","suffix":""}],"badges":[],"createdAt":"2025-11-03 14:05:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8020015/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8020015/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96244106,"identity":"3b50a371-5a15-4982-9597-c5518953bb4f","added_by":"auto","created_at":"2025-11-19 07:17:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":964397,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8020015/v1_covered_5e55133b-70be-48b6-88ea-400d3f919f0d.pdf"},{"id":95901573,"identity":"7f65a201-c4fe-4331-bf39-a1a15428cfa9","added_by":"auto","created_at":"2025-11-14 08:33:34","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":907119,"visible":true,"origin":"","legend":"Extended data figures","description":"","filename":"ExtendedDataFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8020015/v1/6947e0deeead17924b0df5cf.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Volatile food signal activates DHAP shunt to elicit protective fmo-2 response in C. elegans","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8020015/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8020015/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAnimals 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUsing 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur 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. 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