title: Inhibition of adipocyte differentiation by phytoestrogen genistein through a potential downregulation of extracellular signal-regulated kinases 1/2 activity.
abstract: In the current study, we investigated the effects of genistein on adipogenic differentiation of mouse bone marrow-derived mesenchymal stem cell (BMSC) cultures and its potential signaling pathway. The terminal adipogenic differentiation was assessed by western-blotting analysis of adipogenic-specific proteins such as PPARgamma, C/EBPalpha, and aP2 and the formation of adipocytes. Treatment of mouse BMSC cultures with adipogenic cocktail resulted in sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are members of the mitogen-activated protein kinase (MAPK) family, at the early phase of adipogenesis (from days 3 to 9). Inhibition of ERK1/2 activation by PD98059, a specific MEK inhibitor, reversed the induced adipogenic differentiation. Genistein dose-dependently decreased the phosphorylation of ERK1/2 in mouse BMSC cultures. Genistein incubation for the entire culture period, as well as that applied during the early phase of the culture period, significantly inhibited the adipogenic differentiation of mouse BMSC cultures. While genistein was incubated at the late stage (after day 9), no inhibitory effect on adipogenic differentiation was observed. BMSC cultures treated with genistein in the presence of fibroblast growth factor-2 (FGF-2), an activator of the ERK1/2 signaling pathway, expressed normal levels of ERK1/2 activity, and, in so doing, are capable of undergoing adipogenesis. Our results suggest that activation of the ERK1/2 signaling pathway during the early phase of adipogenesis (from days 3 to 9) is essential to adipogenic differentiation of BMSC cultures, and that genistein inhibits the adipogenic differentiation through a potential downregulation of ERK1/2 activity at this early phase of adipogenesis.
authors.affiliation: Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China.
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Liao
authors.forename: Ya-Lin
authors.initials: YL
authors.lastname: Li
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Qin
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
authors.forename: Kang-Kang
authors.initials: KK
authors.lastname: Xu
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
authors.forename: Zhou-Sheng
authors.initials: ZS
authors.lastname: Xiao
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma; D010766:Phosphorylation / Q000187:drug effects; D048789:Phytoestrogens / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D047495:PPAR gamma; D048789:Phytoestrogens; D047428:Protein Kinase Inhibitors; D016222:Fibroblast Growth Factor 2; D019833:Genistein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3