Very long-chain ceramides promote energy expenditure in brown adipose tissue

Very long-chain ceramides promote energy expenditure in brown adipose tissue | 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 Article Very long-chain ceramides promote energy expenditure in brown adipose tissue Judith Simcox, Gina Wade, Isabella James, Ross Soens, Salma Abou Elhassan, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8670360/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Ceramides are increased in the blood in metabolic diseases, including cardiovascular disease and type 2 diabetes. While their cellular roles in insulin resistance and energy metabolism are well established, the functional significance of ceramides in blood plasma remains poorly understood. To address this knowledge gap, we used the selective pressure of acute cold exposure in mice, which rapidly increases very long-chain (VLC) ceramides localized to high-density lipoprotein (HDL) particles. Through heavy labeling, we demonstrated that plasma VLC-ceramides are synthesized in the liver and taken up by brown adipocytes to promote energy expenditure. Inhibition of ceramide synthesis ablates VLC-ceramide production, driving cold intolerance. Mechanistically, HDL-associated VLC-ceramides enhance β3-adrenergic receptor signaling via a previously uncharacterized phosphorylation event, thereby increasing energy expenditure. These results reveal an inter-organ ceramide signaling axis that is dependent on lipoprotein localization and acyl chain length to regulate energy expenditure. Biological sciences/Physiology/Metabolism/Fat metabolism Biological sciences/Molecular biology/Post-translational modifications/Phosphorylation Full Text Additional Declarations There is NO Competing Interest. Supplementary Files allsuppfiguresv5.pdf Supplementary Figures Cite Share Download PDF Status: Posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8670360","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":585221552,"identity":"a7c95049-5eda-4923-a551-bcab22f2af62","order_by":0,"name":"Judith 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