PPAR γ partial agonist, KR-62776, inhibits adipocyte differentiation via activation of ERK

• Published in: Cellular and molecular life sciences : CMLS 2009-05, Vol.66 (10), p.1766-1781
• Main Authors: Kim, J, Han, D. C, Kim, J. M, Lee, S. Y, Kim, S. J, Woo, J. R, Lee, J. W, Jung, S.-K, Yoon, K. S, Cheon, H. G, Kim, S. S, Hong, S. H, Kwon, B.-M
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; adipocyte; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Differentiation - drug effects; Crystallography, X-Ray; ERK; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation; Indans - chemistry; Indans - metabolism; Indans - pharmacology; indenone; Life Sciences; lipolysis; Mice; Models, Molecular; Molecular Structure; Oximes - chemistry; Oximes - metabolism; Oximes - pharmacology; Peroxisome proliferators-activated receptor γ; PPAR gamma - agonists; PPAR gamma - chemistry; PPAR gamma - metabolism; Protein Binding; Protein Structure, Tertiary; Proteome - analysis; Proteome - drug effects; Research Article; Rosiglitazone; Thiazolidinediones - chemistry; Thiazolidinediones - metabolism; Thiazolidinediones - pharmacology
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-009-9169-4

Indenone KR-62776 acts as an agonist of PPARγ without inducing obesity in animal models and cells. X-ray crystallography reveals that the indenone occupies the binding pocket in a different manner than rosiglitazone. 2-Dimensional gel-electrophoresis showed that the expression of 42 proteins was altered more than 2.0-fold between KR-62776- or rosiglitazone-treated adipocyte cells and control cells. Rosiglitazone down-regulated the expression of ERK1/2 and suppressed the phosphorylation of ERK1/2 in these cells. However, the expression of ERK1/2 was up-regulated in KR-62776-treated cells. Phosphorylated ERK1/2, activated by indenone, affects the localization of PPARγ, suggesting a mechanism for indenone-inhibition of adipogenesis in 3T3-L1 preadipocyte cells. The preadipocyte cells are treated with ERK1/2 inhibitor PD98059, a large amount of the cells are converted to adipocyte cells. These results support the conclusion that the localization of PPARγ is one of the key factors explaining the biological responses of the ligands.