Peroxisome Proliferator-activated Receptor γ (PPARγ) as a Molecular Target for the Soy Phytoestrogen Genistein

Zhi-Chao Dang,Valérie Audinot,Socrates E Papapoulos,Jean A Boutin,Clemens W.G.M Löwik

doi:10.1074/jbc.m209483200

Zhi-Chao Dang, Valérie Audinot + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m209483200

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Abstract

The principal soy phytoestrogen genistein has an array of biological actions. It binds to estrogen receptor (ER) alpha and beta and has ER-mediated estrogenic effects. In addition, it has antiestrogenic effects as well as non-ER-mediated effects such as inhibition of tyrosine kinase. Because of its complex biological actions, the molecular mechanisms of action of genistein are poorly understood. Here we show that genistein dose-dependently increases estrogenic transcriptional activity in mesenchymal progenitor cells, but its biological effects on osteogenesis and adipogenesis are different. At low concentrations (< or =1 microm), genistein acts as estrogen, stimulating osteogenesis and inhibiting adipogenesis. At high concentrations (>1 microm), however, genistein acts as a ligand of PPARgamma, leading to up-regulation of adipogenesis and down-regulation of osteogenesis. Transfection experiments show that activation of PPARgamma by genistein at the micromolar concentrations down-regulates its estrogenic transcriptional activity, while activation of ERalpha or ERbeta by genistein down-regulates PPARgamma transcriptional activity. Genistein concurrently activates two different transcriptional factors, ERs and PPARgamma, which have opposite effects on osteogenesis or adipogenesis. As a result, the balance between activated ERs and PPARgamma determines the biological effects of genistein on osteogenesis and adipogenesis. Our findings may explain distinct effects of genistein in different tissues.

Highlights

In recent years, soy phytoestrogens have attracted wide attention due to their potential beneficial effects on some common medical disorders [1,2,3]
We show that genistein dose-dependently increases estrogenic transcriptional activity in mesenchymal progenitor cells, but its biological effects on osteogenesis and adipogenesis are different
At concentrations of 25 ␮M or higher, genistein inhibited ALP activity, nodule formation and Ca2ϩ deposition. These changes were paralleled by mRNA expression of the osteoblastic markers, Cbfa1, osteocalcin, and PTH/PTHrP receptor that, relative to control, were increased by 1 ␮M genistein and decreased by 25 ␮M (Fig. 1)

Summary

Introduction

Soy phytoestrogens have attracted wide attention due to their potential beneficial effects on some common medical disorders [1,2,3]. We show that genistein dose-dependently increases estrogenic transcriptional activity in mesenchymal progenitor cells, but its biological effects on osteogenesis and adipogenesis are different. Genistein concurrently activates two different transcriptional factors, ERs and PPAR␥, which have opposite effects on osteogenesis or adipogenesis.

Results

Conclusion