ZFIN ID: ZDB-PUB-140513-431
KR-62980 Suppresses Lipid Metabolism Through Inhibition of Cytosolic NADP Isocitrate Dehydrogenase in Zebrafish
Chun, H.S., Shin, S.H., Ahn, S., Shin, D.S., Choi, S.S., Ahn, J.H., Bae, M.A.
Date: 2014
Source: Zebrafish   11: 122-8 (Journal)
Registered Authors: Chun, Hang-Suk
Keywords: none
MeSH Terms:
  • 3T3-L1 Cells
  • Animals
  • Cell Line
  • Gene Expression/drug effects*
  • Indenes/pharmacology*
  • Isocitrate Dehydrogenase/genetics*
  • Isocitrate Dehydrogenase/metabolism
  • Lipid Metabolism/drug effects*
  • Mice
  • Morpholines/pharmacology*
  • PPAR gamma/agonists
  • Polymerase Chain Reaction
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Zebrafish/genetics*
  • Zebrafish/metabolism*
PubMed: 24588364 Full text @ 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.