Limiting De Novo Lipogenesis Unlocks the Thermogenic Potential of Glucose in Brown Fat

Limiting De Novo Lipogenesis Unlocks the Thermogenic Potential of Glucose in Brown Fat | 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 Limiting De Novo Lipogenesis Unlocks the Thermogenic Potential of Glucose in Brown Fat Yuliya Skorobogatko, Farid Rezayat, Regina Zhang, Maxim Pustovoitov, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8790643/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 While glucose uptake is a surrogate marker of brown fat activation, its role in thermogenesis remains uncertain. To ascertain when and how glucose can fuel thermogenesis, we generated brown adipocyte-specific RalGAPB knockout (KO) mice, which have constitutively active RalA and dramatically elevated glucose uptake due to the translocation of the glucose transporter Glut4 to the plasma membrane (PM). Lean mice with RalGAPB KO showed increased lipid accumulation in brown adipocytes through elevated de novo lipogenesis (DNL) and reduced oxidative metabolism; these mice exhibited markedly reduced energy expenditure and cold tolerance. DNL inhibitors rescued the defective oxidation and energy expenditure in the KO mice. Surprisingly, brown adipocyte DNL was not increased in obese RalGAPKO mice, but energy expenditure was. Moreover, obese KO mice lost more fat than controls during fasting, due to a combination of increased energy expenditure and reduced insulin levels that favored systemic lipid oxidation. RalA was activated in brown fat by β adrenergic stimulation due to increased insulin secretion, an effect that was required for cold tolerance. This process was repressed in obesity. Together, these findings reveal that increasing glucose uptake drives energy expenditure when DNL is restricted, underscoring the context-dependent role of glucose metabolism in brown fat thermogenesis. Biological sciences/Physiology/Metabolism/Fat metabolism Biological sciences/Physiology/Metabolism/Metabolic diseases/Obesity Biological sciences/Physiology/Metabolism/Homeostasis Full Text Additional Declarations There is NO Competing Interest. 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-8790643","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":587110543,"identity":"e04b9004-8925-4a98-8e67-6efec8b301f0","order_by":0,"name":"Yuliya 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To ascertain when and how glucose can fuel thermogenesis, we generated brown adipocyte-specific RalGAPB knockout (KO) mice, which have constitutively active RalA and dramatically elevated glucose uptake due to the translocation of the glucose transporter Glut4 to the plasma membrane (PM). Lean mice with RalGAPB KO showed increased lipid accumulation in brown adipocytes through elevated \u003cem\u003ede novo\u003c/em\u003e lipogenesis (DNL) and reduced oxidative metabolism; these mice exhibited markedly reduced energy expenditure and cold tolerance. DNL inhibitors rescued the defective oxidation and energy expenditure in the KO mice. Surprisingly, brown adipocyte DNL was not increased in obese RalGAPKO mice, but energy expenditure was. Moreover, obese KO mice lost more fat than controls during fasting, due to a combination of increased energy expenditure and reduced insulin levels that favored systemic lipid oxidation. 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