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 PPARγ, C/EBPα, 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.

Feeding soy protein isolate and treatment with estradiol have different effects on mammary gland morphology and gene expression in weanling male and female rats

“…Reduced abdominal fat and mammary adipocyte size have previously been observed in the female mammary gland at PND50 after longer periods of developmental SPI exposure beginning with the dams during gestation (56). Isoflavones and E2 are both recognized to inhibit adipogenesis and reduce fat cell size (8,28,36,38,56). Reductions in adiposity might be mediated via isoflavone activation of a subset of estrogen receptor-mediated pathways or alternately through other pathways such as inhibition of sterol receptor element binding protein (SREBP-1c)-mediated fatty acid synthesis or activation of the nuclear receptor PPAR-␣ to increase fatty acid metabolism (44).…”

“…Genistein is a well-described inhibitor of the MAPK phosphatase Dusp1 (33,34), which was also reported to be downregulated by equol (4). Expression of the transcription factor Cebpa was also found to be reduced following genistein treatment (28,38). Dusp1 and Cebpa, as well as two other SPI downregulated genes in males, Aebp1 and Fgfr1, are positive regulators of ERK1/2-mediated adipogenesis (21,28,38,39,61).…”

“…Expression of the transcription factor Cebpa was also found to be reduced following genistein treatment (28,38). Dusp1 and Cebpa, as well as two other SPI downregulated genes in males, Aebp1 and Fgfr1, are positive regulators of ERK1/2-mediated adipogenesis (21,28,38,39,61). Along with the observed decrease in serum insulin (59) and body weight (44,56), the downregulation observed in these genes is consistent with a reduction in mammary gland adipogenesis in SPI-fed rats that has previously been reported in female rats fed SPI throughout early development (56).…”

17β-Estradiol inhibition of PPARγ-induced adipogenesis and adipocyte-specific gene expression

“…Similarly, other research has shown that E and E-like compounds inhibited the DNA-binding activity of PPARγ and that nuclear extracts isolated from adipose tissues of ERβ-KO mice showed increased binding of endogenous PPARγ in comparison with wild-type mice [26] . PPARγ-binding activity was also markedly decreased in the phytoestrogen genistein-treated cells compared with untreated control [39] . The mammalian two-hybrid assay showed that E significantly decreased the troglitazone-induced CBP association in the presence of ERα or ERβ and that this effect was more prominent by ERβ.…”

Extracellular regulated protein kinases 1/2 phosphorylation is required for hepatic differentiation of human umbilical cord-derived mesenchymal stem cells

“…[28][29][30] Inhibition of the ERK1/2 pathway can increase ALP activity, and that mineralization in skeletal muscle-derived stem cells leads to osteogenesis. 31 Hepatic differentiation is tightly regulated by cytokines and growth factors through signaling events.…”