Peroxisome proliferator-activated receptor gamma (PPARgamma ) as a molecular target for the soy phytoestrogen genistein.
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.
Dang
Zhi-Chao
ZC
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, The Netherlands.
Audinot
Valérie
V
Papapoulos
Socrates E
SE
Boutin
Jean A
JA
Löwik
Clemens W G M
CW
D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects*
D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D014157:Transcription Factors; D019833:Genistein