Abstract
Although stem cells from mice deficient of FGF2 have been reported to display enhanced capacity for adipogenesis, the literature using in vitro cell culture system has so far reported conflicting results on the role of FGF2 in adipogenesis. We here demonstrate that FGF2, depending on concentration, can function as either a positive or negative factor of in vitro adipogenesis by regulating activation of the ERK signaling pathway. FGF2 at concentrations lower than 2 ng/ml enhanced in vitro adipogenesis of human adipose-derived stem cells (hASCs). However, FGF2 at concentrations higher than 10 ng/ml was able to suppress adipogenesis by maintaining sustained phosphorylation of ERK and function as a dominant negative adipogenic factor toward BMP ligands. Expression levels of FGF2 in the fat tissues from high fat diet induced obese C57BL/6 mice were lower than those from normal chow diet mice, indicating that expression levels of FGF2 in the fat tissues might be in reverse correlation with the size of fat tissues. Our observation of concentration dependent biphasic effect as well as dominant negative effect of FGF2 on adipogenesis provides a mechanistic basis to understand roles of FGF2 in adipogenesis and development of fat tissues.
Highlights
Adipogenesis, which determines differentiation of fibroblast-like mesenchymal precursor stem cells into lipid-laden and insulin-responsive adipocytes, requires networks of signaling pathways [1,2,3] and extracellular factors [4]
In order to analyze dose-dependent effects of FGF1 and FGF2 on adipogenesis, human ASCs were preconditioned with different concentrations of the FGF ligands in the growth medium for 1 day and subsequently grown in the differentiation medium without the FGF ligands for 7 days
Whereas FGF1 enhanced expression of adipocyte protein 2, an adipogenic marker protein, in a dose dependent manner, FGF2 enhanced it at concentrations 0.4 ~ 2 ng/ml but suppressed at concentrations 10 ng/ml and higher (Fig. 1A)
Summary
Adipogenesis, which determines differentiation of fibroblast-like mesenchymal precursor stem cells into lipid-laden and insulin-responsive adipocytes, requires networks of signaling pathways [1,2,3] and extracellular factors [4]. The mitogen activating protein kinase (MAPK) signaling pathway has been identified to regulate differentiation of stem cells into adipocytes. Phosphorylation of PPARγ by ERK suppresses PPARγ activity, and ERK needs to be shut-off to proceed with maturation of adipocytes [6,7]. Activity of ERK during adipogenesis is regulated by two proteins, DUSP-1 and AE binding protein (AEBP)-1. Expression of dual specificity protein phosphatase-1 (DUSP-1), which inactivates ERK, is up-regulated in mature adipocytes [9]. AEBP-1, which binds to ERK and protects from phosphatases, is down-regulated in mature adipocytes [6]
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