title: A newly identified CG301269 improves lipid and glucose metabolism without body weight gain through activation of peroxisome proliferator-activated receptor alpha and gamma.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo.
  
  
  METHODS
  Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR.
  
  
  RESULTS
  CG301269 selectively stimulated the transcriptional activities of PPARα and PPARγ. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain.
  
  
  CONCLUSIONS
  We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders.
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology & Genetics, Seoul National University, Seoul, Korea.
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Jeong
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Kim
authors.forename: Sung Sik
authors.initials: SS
authors.lastname: Choe
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Ho Seon
authors.initials: HS
authors.lastname: Park
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Shin
authors.forename: Gha Young
authors.initials: GY
authors.lastname: Lee
authors.forename: Dongkyu
authors.initials: D
authors.lastname: Shin
authors.forename: Hanjae
authors.initials: H
authors.lastname: Lee
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Eun Bok
authors.initials: EB
authors.lastname: Choi
authors.forename: Hyeon Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Heekyoung
authors.initials: H
authors.lastname: Chung
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Seonggu
authors.initials: S
authors.lastname: Ro
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D050260:Carbohydrate Metabolism / Q000187:drug effects*; D002460:Cell Line; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053778:Thiazolidines / Q000494:pharmacology*; D014162:Transfection
chemical_list: C556443:CG 301269; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D053778:Thiazolidines; D005947:Glucose