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However, current PPAR\u03b3-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified a small molecular compound, F12016, as a selective PPAR\u03b3 agonist by virtual screening, which showed moderate PPAR\u03b3 agonistic activity and binding ability for PPAR\u03b3. F12016 did not activate other PPAR subtypes at 30\u2005\u03bcM and selectively modulated PPAR\u03b3 target gene expression. In diabetic KKAy mice, F12016 had insulin-sensitizing and glucose-lowering properties and suppressed weight gain. In vitro, F12016 effectively increased glucose uptake and blocked cyclin-dependent kinase 5-mediated phosphorylation of PPAR\u03b3 at Ser273, but slightly triggered adipogenesis and less inhibited osteoblastogenesis than rosiglitazone. Moreover, compared with the full agonist rosiglitazone, F12016 had a distinct group of coregulators and a different predicted binding mode for the PPAR\u03b3 ligand-binding domain. A site mutation assay confirmed the key epitopes, especially Tyr473 in AF-2. In summary, our study shows that F12016 is a non-TZD, novel selective PPAR\u03b3 agonist without the classical lipogenic side effects, which may provide a new structural strategy for designing PPAR\u03b3 ligands with advantages over TZDs.<\/jats:p>","DOI":"10.1038\/srep09530","type":"journal-article","created":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T06:35:06Z","timestamp":1427870106000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Identification of a novel selective agonist of PPAR\u03b3 with no promotion of adipogenesis and less inhibition of osteoblastogenesis"],"prefix":"10.1038","volume":"5","author":[{"given":"Chang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningyu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanni","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Si","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,4,1]]},"reference":[{"key":"BFsrep09530_CR1","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1172\/JCI28003","volume":"116","author":"RK Semple","year":"2006","unstructured":"Semple, R. 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