IGF binding protein-3 and obesity: How does IGFBP-3 prevent the differentiation of mesenchymal stem cells into adipocytes?
Summary
This project will build on our previous studies showing that insulin-like growth factor binding protein-3 (IGFBP-3) inhibits adipocyte differentiation, by examining the factors involved in adipocyte formation from mesenchymal stem cells, and the way this process is affected by IGFBP-3 and other growth-regulatory proteins.
Supervisor(s)
Research Location
Kolling Institute of Medical Research
Program Type
PHD
Synopsis
Insulin-like growth factor binding protein-3 (IGFBP-3) is one of six IGFBPs that transport IGFs in the circulation, and affect cell growth, differentiation, motility and survival through a range of mechanisms. Although IGFBP-3 binds IGF-I and IGF-II with high affinity, some of its cellular effects occur through interactions with other, non-IGF ligands. The nuclear receptor, retinoid X receptor (RXR) is one such ligand. RXR affects a wide variety of cellular functions by dimerising with other nuclear receptors including retinoic acid receptor (RARa), vitamin D receptor (VDR), and peroxisome proliferator-activated receptor-g (PPARg). These receptor heterodimers affect the transcription of many genes in a wide range of cell types. The current obesity epidemic has led to increased interest in the regulation of fat cell formation (adipogenesis). As one of the “master regulators” of adipogenesis, the regulation of PPARg is particularly important in adipose tissue. In a previous PhD project in this laboratory, it was found that IGFBP-3 binds directly to PPARg as well as RXRa, prevents their dimerisation, blocks their transcriptional activity, and prevents the differentiation of preadipocytes into mature adipocytes. This new PhD project will examine fat cell formation from an earlier precursor cell type, the mesenchymal progenitor or stem cell (MSC). These multipotent cells have the potential to form into bone and cartilage as well as adipose tissue, and the factors that regulate these differentiation pathways are only partially understood. This project will examine the ability of IGFBP-3 to inhibit adipogenesis and whether it promotes differentiation along an alternative pathway. The project, involving the use of both human and mouse MSC lines, will examine the regulation of IGFBP-3 expression during differentiation, and the effect of modulating this expression by downregulation or overexpression. It will examine IGFBP-3 effects on the adipogenesis inhibitor PREF1 and adipogenesis initiators of the C/EBP (CCAAT enhancer-binding protein) family, and will use a range of endpoints of adipogenic differentiation including cell morphology, fat accumulation, and the induction of gene expression including adiponectin, PPARg and resistin. This study will seek to integrate the growing list of IGFBP-3 ligands and IGFBP-3-regulated genes into an integrated model of the role of IGFBP-3 in regulating adipocyte formation from multipotent precursor cells. It thus has the potential to provide a very novel approach to understanding the regulation of adipogenesis.
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Keywords
adipocyte, Differentiation, mesenchymal, stem cell, IGFBP-3, insulin-like, growth factor, IGF, Obesity, nuclear receptor
Opportunity ID
The opportunity ID for this research opportunity is: 992
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