{"paper_id":"3f2b4b1c-a083-420e-bbff-5ba2549b841b","body_text":"Purinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic 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 Purinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic brown adipose tissue Joerg Heeren, Michelle Y. Jaeckstein, Alexander Fischer, Björn Rissiek, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6246705/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 Loss of brown adipose tissue (BAT) activity observed during ageing, obesity and living at thermoneutrality is associated with lipid accumulation, fibrosis and tissue inflammation in BAT. The mechanisms that promote this degenerative process of BAT involution remain largely enigmatic. Here, we show that an imbalance between sympathetic activation and mitochondrial energy handling causes BAT degeneration, which leads to impaired energy expenditure and systemic metabolic disturbances. Mechanistically, we demonstrate that brown adipocytes secrete ATP in response to imbalanced thermogenic activation, which activates P2X4 and P2X7 of BAT-resident macrophages. Notably, mice lacking activity of these purinergic receptors in myeloid cells are protected against BAT inflammation, thermogenic dysfunction and systemic metabolic disturbances under conditions of imbalanced BAT activation, thermoneutrality or overnutrition. These results highlight the relevance of extracellular ATP released by brown adipocytes as a paracrine signal for myeloid cells to initiate BAT involution. Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity Health sciences/Molecular medicine Health sciences/Endocrinology/Endocrine system and metabolic diseases/Pre-diabetes Full Text Additional Declarations There is NO Competing Interest. 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. 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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-6246705\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":443474594,\"identity\":\"360bf8ea-eb4f-4be6-a5c4-124d747f8c72\",\"order_by\":0,\"name\":\"Joerg Heeren\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAq0lEQVRIiWNgGAWjYBACAwhlwyABJCVI0ZJGupbDJGgxZ28+9uHjjvOJM9sbGG98IEaLZc+x5Jkzz9xOnM1zgNlyBlEOu5FjzMzbdjtxnkQCmzQPUVruv//M/LftXOI8+Qds0n+Is4WHmZmx7UDibAkGNmlidDAYnEkzZuxtSzae2ZPYbNlDlJbjhx8z/Gyzk51x/PDBGz+IsgYBGBtI1DAKRsEoGAWjACcAABE5MwzHNEtgAAAAAElFTkSuQmCC\",\"orcid\":\"https://orcid.org/0000-0002-5647-1034\",\"institution\":\"University Medical Center Hamburg-Eppendorf\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Joerg\",\"middleName\":\"\",\"lastName\":\"Heeren\",\"suffix\":\"\"},{\"id\":443474595,\"identity\":\"76fd9119-1ef6-4cc8-a2df-2a04f7296414\",\"order_by\":1,\"name\":\"Michelle Y. 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