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

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.
AuthorsHang-Suk Chun, Sun Hye Shin, Sunjoo Ahn, Dae-Seop Shin, Sun-Sil Choi, Jin Hee Ahn, Myung Ae Bae
JournalZebrafish (Zebrafish) Vol. 11 Issue 2 Pg. 122-8 (Apr 2014) ISSN: 1557-8542 [Electronic] United States
PMID24588364 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 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+)
  • 3T3-L1 Cells
  • Animals
  • Cell Line
  • Gene Expression (drug effects)
  • Indenes (pharmacology)
  • Isocitrate Dehydrogenase (genetics, metabolism)
  • Lipid Metabolism (drug effects)
  • Mice
  • Morpholines (pharmacology)
  • PPAR gamma (agonists)
  • Polymerase Chain Reaction
  • RNA, Messenger (genetics, metabolism)
  • Zebrafish (genetics, metabolism)

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