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Inhibition of adipocyte differentiation by insulin-like growth factor-binding protein-3

¹Kolling Institute of Medical Research, Royal North Shore Hospital, and ²Discipline of Medicine, University of Sydney, New South Wales, Australia

Submitted 16 October 2008 ; accepted in final form 7 January 2009

Insulin-like growth factor-binding protein-3 (IGFBP-3) interacts with the type II nuclear receptors retinoid X receptor (RXR) and retinoic acid receptor- and modulates their transcriptional activity. Peroxisome proliferator-activated receptor (PPAR), a related nuclear receptor that dimerizes with RXR, 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 PPAR-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 RXR or PPAR, decreased markers of adipocyte differentiation, PPAR, 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 PPAR in vitro and in 3T3-L1 adipocyte lysates and inhibited PPAR heterodimerization with RXR 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 PPAR system suggests a role for IGFBP-3 in the pathogenesis of obesity and insulin resistance.

3T3-L1 cells; peroxisome proliferator-activated receptor-; insulin-like growth factor-binding protein-3

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				P. M. Yamada and K.-W. Lee Perspectives in mammalian IGFBP-3 biology: local vs. systemic action Am J Physiol Cell Physiol, May 1, 2009; 296(5): C954 - C976. [Abstract] [Full Text] [PDF]