{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:21:12Z","timestamp":1789759272303,"version":"4.0.1"},"posted":{"date-parts":[[2025,12,16]]},"group-title":"Cell Biology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["NIH R01DK128848"],"award-info":[{"award-number":["NIH R01DK128848"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DK130174"],"award-info":[{"award-number":["R01DK130174"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DK112943"],"award-info":[{"award-number":["R01DK112943"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The nuclear receptor PPAR\u03b3 is a primary therapeutic target for insulin resistance and type 2 diabetes (T2D); however, its thiazolidinedione (TZD) class of PPAR\u03b3 agonists have substantial safety concerns in clinical utilization. Genetic inhibition of PPAR\u03b3 acetylation at K268 and K293 dissociates the major adverse effects of TZDs from insulin sensitization and other metabolic improvements. We therefore posit that chemical inhibition of PPAR\u03b3 acetylation would elicit insulin sensitization with improved safety. Here we describe the identification of a synthetic thiopyrimidine derivative (TPMD) that acts as a small molecule inhibitor of PPAR\u03b3 acetylation. TPMD improves insulin sensitivity, promotes brown remodeling of white adipose tissue (WAT), increases energy expenditure, and decreases adiposity in dietary and genetic mouse models of T2D. Importantly, TPMD is deprived of the major side effects of TZDs, including weight gain, fluid retention, cardiac hypertrophy, bone marrow adiposity, and bone loss. X-ray crystallography at 2.0 \u00c5 resolution reveals a unique binding mode of TPMD molecules to the PPAR\u03b3 ligand-binding domain and provides structural and molecular basis for the acetylation inhibitory activity of TPMD together with site-directed mutagenesis studies. These findings identify TPMD as a first-in-class compound that specifically targets PPAR\u03b3 acetylation and possesses the potential of developing into a safe insulin sensitizer to treat and prevent T2D and obesity.<\/jats:p>","DOI":"10.64898\/2025.12.15.694265","type":"posted-content","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T08:00:32Z","timestamp":1765958432000},"source":"Crossref","is-referenced-by-count":1,"title":["Small molecule inhibitor of PPAR\u03b3 acetylation promotes insulin sensitization and browning of white adipose tissue with improved safety"],"prefix":"10.64898","author":[{"given":"Dan","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkateswararao","family":"Eeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianfen","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oana","family":"Herlea-Pana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ying","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne 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