Inhibition of adipocyte differentiation by insulin-like growth factor-binding protein-3.
Insulin-like growth factor-binding protein-3 (IGFBP-3) interacts with the type II nuclear receptors retinoid X receptor (RXR)alpha and retinoic acid receptor-alpha and modulates their transcriptional activity. Peroxisome proliferator-activated receptor (PPAR)gamma, a related nuclear receptor that dimerizes with RXRalpha, plays an important role in adipocyte differentiation. IGFBP-3 is regulated during adipocyte differentiation, but its role in this process is unknown. We demonstrate that IGFBP-3 interferes with the PPARgamma-dependent processes of adipocyte differentiation and maintenance of the gene expression characteristic of mature adipocytes. Treatment of adipocytes with exogenous IGFBP-3, but not an IGFBP-3 mutant that does not bind RXRalpha or PPARgamma, decreased markers of adipocyte differentiation, PPARgamma, and resistin but increased the preadipocyte marker plasminogen activator inhibitor-1. Furthermore, expression of human IGFBP-3, but not the IGFBP-3 mutant, by preadipocytes inhibited preadipocyte differentiation as determined by gene markers and lipid accumulation. IGFBP-3 interacted with PPARgamma in vitro and in 3T3-L1 adipocyte lysates and inhibited PPARgamma heterodimerization with RXRalpha in vitro. Wild-type IGFBP-3, but not mutant IGFBP-3, blocked ligand-induced transactivation of PPAR response element in 3T3-L1 cells. The observation that IGFBP-3 inhibits adipocyte differentiation and impacts on the PPARgamma system suggests a role for IGFBP-3 in the pathogenesis of obesity and insulin resistance.
Chan
Sophie S Y
SS
Kolling Institute of Medical Research, Royal North Shore Hospital, and Discipline of Medicine, University of Sydney, St Leonards, NSW 2065, Australia.
Schedlich
Lynette J
LJ
Twigg
Stephen M
SM
Baxter
Robert C
RC
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000494:pharmacology; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014162:Transfection
D007004:Hypoglycemic Agents; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D050505:Mutant Proteins; D011994:Recombinant Proteins; D045162:Thiazolidinediones; C039671:ciglitazone