title: L312, a novel PPARγ ligand with potent anti-diabetic activity by selective regulation.
abstract: BACKGROUND
  Selective PPARγ modulators (sPPARγM) 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 PPARγ in vitro, respectively. And the anti-diabetic effects and underlying molecular mechanisms of L312 was studied in db/db mice.
  
  
  RESULTS
  L312 interacted with PPARγ-LBD in a manner similar to known sPPARγM. L312 showed similar PPARγ binding affinity, but displayed partial PPARγ agonistic activity compared to PPARγ 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 PPARγ phosphorylation and displayed a selective gene expression profile in epididymal WAT.
  
  
  CONCLUSIONS
  L312 is a novel sPPARγM.
  
  
  CONCLUSIONS
  L312 may represent a novel lead for designing ideal sPPARγM for T2DM treatment with advantages over current TZDs.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xinni
authors.initials: X
authors.lastname: Xie
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xinbo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Long
authors.initials: L
authors.lastname: Long
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: wangll63@126.com.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
mesh_terms: D041721:3T3-L1 Cells; D052436:Adipose Tissue, White / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D015153:Blotting, Western; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D012694:Serine; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D000077205:Pioglitazone
keywords: Insulin resistance; Selective PPARγ modulator; pSer273PPARγ