title: KR-62980 suppresses lipid metabolism through inhibition of cytosolic NADP isocitrate dehydrogenase in zebrafish.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) is a target of antidiabetic drugs. However, many PPARγ activators, including rosiglitazone, show unwanted side effects, such as weight gain. The KR-62980 [1-(trans-methylimino-N-oxy)-3-phenyl-6-(3-phenylpropoxy)-1H-indene-2-carboxylic acid ethyl ester], a novel partial agonist of PPARγ, is a new compound for diabetes with antihyperglycemic activity and weak antiadipogenic activity. This study was performed to elucidate the mechanism of the weak adipogenesis induced by KR-62980 despite its being a PPARγ agonist in zebrafish. We elucidated the mechanism of KR-62980 in lipid metabolism using adipocytes and zebrafish. Since NADPH is a critical cofactor in fat metabolism, we investigated effect of KR-62980 on NADPH-producing enzymes such as cytosolic NADP(+) isocitrate dehydrogenase (cICDH). We found that the mRNA expression of cICDH was significantly decreased by KR-62980 in 3T3-L1 cells. KR-62980 inhibited lipase activity and lipid metabolism in zebrafish. Further, KR-62980 substantially suppressed cICDH in adipocytes and zebrafish. These results suggest that cICDH may be one of the targets of KR-62980 responsible for weight gain and adipogenesis.
authors.affiliation: Drug Discovery Platform Technology Team, Korea Research Institute of Chemical Technology , Daejeon, Republic of Korea.
authors.forename: Hang-Suk
authors.initials: HS
authors.lastname: Chun
authors.forename: Sun Hye
authors.initials: SH
authors.lastname: Shin
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.forename: Dae-Seop
authors.initials: DS
authors.lastname: Shin
authors.forename: Sun-Sil
authors.initials: SS
authors.lastname: Choi
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects*; D007192:Indenes / Q000494:pharmacology*; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism*
chemical_list: C513115:1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester; D007192:Indenes; D009025:Morpholines; D047495:PPAR gamma; D012333:RNA, Messenger; D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+)