KR-62980 suppresses lipid metabolism through inhibition of cytosolic NADP isocitrate dehydrogenase in zebrafish

Zebrafish. 2014 Apr;11(2):122-8. doi: 10.1089/zeb.2013.0919. Epub 2014 Mar 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

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*

Substances

  • 1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester
  • Indenes
  • Morpholines
  • PPAR gamma
  • RNA, Messenger
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase (NADP+)