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

Abstract

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.

Hepatic Gene Networks in Morbidly Obese Patients With Nonalcoholic Fatty Liver Disease

“…The insulinlike growth factor binding protein 3 (IGFBP3) is one of six high-affinity binding proteins for IGFs that reduce the levels of free IGF and antagonize their insulin-like activity. It interferes with adipocyte differentiation [61] and also interferes with insulin and glucose homeostasis resulting in impaired glucose tolerance and insulin resistance [62,63]. IGFBP3 has IGF-independent cellular activities such control of cell growth and apoptosis [64,65].…”

The Insulin-like Growth Factor-1 Binding Protein Acid-labile Subunit Alters Mesenchymal Stromal Cell Fate

“…Although the stabilizing influence of the binary and ternary complexes on insulin-like growth factor-1 (IGF-1) in serum are well known, little effort has been devoted to determining what possible autocrine/paracrine roles the IGF-1 binding proteins have in marrow (22)(23)(24)(25). Binding proteins, such as IGFBP-3 and the ALS, are found locally in tissue and fluid compartments, in and out of serum in both mice and humans (18,26).…”

Targeting Insulin-Like Growth Factor-I and Insulin-Like Growth Factor–Binding Protein-3 Signaling Pathways. A Novel Therapeutic Approach for Asthma

“…Although IGFBP-3 has been known to inhibit cell growth and/or promote apoptosis, it can promote cell growth in various cell types (91,92). In addition, IGFBP-3 has other functional roles, such as a proangiogenic effect on endothelial precursor cells (42), induction of a fibrotic phenotype in fibroblasts in vitro (43,93), inhibition of human preadipocyte differentiation and differentiated adipocyte function (94), and anti-inflammatory actions in vivo and in vitro (8,9,95).…”