| First Author | Xie X | Year | 2015 |
| Journal | Biochim Biophys Acta | Volume | 1850 |
| Issue | 1 | Pages | 62-72 |
| PubMed ID | 25305559 | Mgi Jnum | J:251545 |
| Mgi Id | MGI:6100496 | Doi | 10.1016/j.bbagen.2014.09.027 |
| Citation | Xie X, et al. (2015) L312, a novel PPARgamma ligand with potent anti-diabetic activity by selective regulation. Biochim Biophys Acta 1850(1):62-72 |
| abstractText | BACKGROUND: Selective PPARgamma modulators (sPPARgammaM) retains insulin sensitizing activity but with minimal side effects compared to traditional TZDs agents, is thought as a promising strategy for development of safer insulin sensitizer. METHODS: We used a combination of virtual docking, SPR-based binding, luciferase reporter and adipogenesis assays to analyze the interaction mode, affinity and agonistic activity of L312 to PPARgamma in vitro, respectively. And the anti-diabetic effects and underlying molecular mechanisms of L312 was studied in db/db mice. RESULTS: L312 interacted with PPARgamma-LBD in a manner similar to known sPPARgammaM. L312 showed similar PPARgamma binding affinity, but displayed partial PPARgamma agonistic activity compared to PPARgamma full agonist pioglitazone. In addition, L312 displayed partial recruitment of coactivator CBP yet equal disassociation of corepressor NCoR1 compared to pioglitazone. In db/db mice, L312 (30 mg/kg.day) treatment considerably improved insulin resistance with the regard to OGTT, ITT, fasted blood glucose, HOMA-IR and serum lipids, but elicited less weight gain, adipogenesis and hemodilution compared with pioglitazone. Further studies demonstrated that L312 is a potent inhibitor of CDK5-mediated PPARgamma phosphorylation and displayed a selective gene expression profile in epididymal WAT. CONCLUSIONS: L312 is a novel sPPARgammaM. GENERAL SIGNIFICANCE: L312 may represent a novel lead for designing ideal sPPARgammaM for T2DM treatment with advantages over current TZDs. |
