The Histone Demethylase KDM6B Governs the LYVE1+ Perivascular Macrophage Phenotype to Control Adipose Tissue Expandability through BMP2 signaling

The Histone Demethylase KDM6B Governs the LYVE1+ Perivascular Macrophage Phenotype to Control Adipose Tissue Expandability through BMP2 signaling | 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 The Histone Demethylase KDM6B Governs the LYVE1+ Perivascular Macrophage Phenotype to Control Adipose Tissue Expandability through BMP2 signaling Nicolas Venteclef, Bastien AZNAR, Zaineb Mezdari, Jialing He, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7071720/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 The capacity of white adipose tissue (WAT) to expand in response to energy surplus is a key factor in determining metabolic health. In obesity, this expansion becomes dysregulated and contributes to metabolic dysfunction, insulin resistance and type 2 diabetes. Phenotypically diverse subtypes of adipose tissue macrophages (ATMs) control WAT plasticity, yet the underlying regulatory mechanisms and factors have remained enigmatic. Here, we identify the lysine demethylase KDM6B (aka JMJD3) as an essential epigenetic and transcriptional regulator that specifies ATM phenotypes during WAT expansion. We first show that KDM6B expression in human ATMs correlates with insulin sensitivity, glycemic control and levels of WAT inflammation. Single-cell RNA sequencing of both human and mouse ATMs revealed that KDM6B is predominantly expressed in LYVE1⁺CD206⁺ perivascular macrophages (PVMs), where it is essential for their maintenance and endocytic function. Myeloid-specific depletion of Kdm6b in mice triggers a phenotypic shift of PVMs, resulting in accumulation of CD9⁺CD63⁺ lipid-associated macrophages (LAMs) and impaired WAT expansion marked by adipocyte hypertrophy, vascular rarefaction and increased inflammation. Consequently, Kdm6b-deficient mice develop pronounced insulin resistance and a pro-diabetic state when exposed to a high-fat diet. We uncover that KDM6B governs the transcriptional program of PVMs, including the regulation of adipogenesis, through BMP2 signaling. Mechanistically, KDM6B directly regulates Bmp2 expression in PVMs through demethylation of H3K27me3 at the Bmp2 promoter. Myeloid-specific depletion of Bmp2 partially mimics the WAT phenotype seen in Kdm6b-deficient mice, characterized by adipocyte hypertrophy. Overall, our study identifies the KDM6B–BMP2 axis as an ATM-intrinsic epigenetic and transcriptional regulator that couples immune cell phenotypes to WAT expandability and metabolic health. Biological sciences/Physiology/Metabolism/Fat metabolism Biological sciences/Cell biology/Mechanisms of disease Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryFiguresandTables0707.pdf Supplementary Figures and Tables 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. 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-7071720","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":490711447,"identity":"fbf39404-6dc2-4db7-9c54-78a9045d761d","order_by":0,"name":"Nicolas 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