GRANT=P01AG24387-01 Relative consumption of the estrogenic soy isoflavones genistein and daidzein in infants fed soy-based formula is 10-fold greater than in adults eating high-soy diets. Estrogens play key inhibitory roles in adipocyte differentiation and establishment of adult adipocyte numbers, as shown by the over 100% increase in fad pad mass and adipocyte numbers in mice lacking endogenous estrogen production or estrogen receptor (ER) alpha. This suggest that genistein could affect adipogenic differentiation and adult adipocyte number in human infants fed soy formula, a possibility consistent with our Preliminary Results indicating that dietary genistein inhibits PPARgamma concentrations can stimulate adipogenesis by increasing PPARgamma and acting as a PPARgamma ligand, effects not mediated through ER. This raises the possibility that high levels of genistein could increase adipocyte number through non-ER-mediated mechanism, though low levels inhibit adipogenic development through ER. This raises the possibility that high levels of genistein could increase adipocyte number though non-ER-mediated mechanism, though low levels inhibit adipogenic development through ER. The central hypothesis of this proposal is that neonatal exposure to the phytoestrogen genistein will produce important dose-dependent alterations in adipocyte differentiation that could have lasting effects on adiposity in adults and might have profound effects on glucose and insulin metabolism during later adulthood. To test this hypothesis, a physiologically relevant system involving dietary administration of genistein to dams will be used to determine if genistein exposure in pups results in adult changes in adipocyte number, adiposity and/or metabolism, and if these effects persist or are exacerbated in aged animals. To analyze the mechanistic basis of this effect, we will determine quantitative and temporal changes in gene expression induced by genistein exposure of mouse embryonic fibroblasts induced to differentiate as adipocytes, and determine if genistein effects are mediated through ER and involve changes in PPARgamma and/or the cell cycle regulators p27/kip1 and p21/Cip1. The proposed research represents a structured approach to defining effects of genistein exposure on adipose development its mechanistic basis. This work, along with other projects in this proposal that will seek to evaluate the effects of soy isoflavones on other organ systems and the roles that they play in the aging process, will extend our knowledge of potential human health effects of phytoestrogens and allow more informed decisions to be made about the desirability of phytoestrogen consumption in various scenarios.
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