DIETARY PHYTOESTROGENS AND ADIPOCYTE DEVELOPMENT

授予= P01 AG 24387 -01 食用大豆配方奶粉的婴儿体内雌激素大豆异黄酮和大豆黄酮的相对消耗量是食用高大豆饮食的成年人的10倍。雌激素在脂肪细胞分化和成年脂肪细胞数量的建立中起关键的抑制作用，如缺乏内源性雌激素产生或雌激素受体（ER）α的小鼠中脂肪垫质量和脂肪细胞数量增加超过100%所示。这表明染料木黄酮可以影响喂养大豆配方的人类婴儿的成脂分化和成年脂肪细胞数量，这一可能性与我们的初步结果一致，表明膳食染料木黄酮抑制PPARgamma浓度可以通过增加PPARgamma和作为PPARgamma配体刺激脂肪形成，这种作用不是通过ER介导的。这增加了高水平的染料木黄酮可以通过非ER介导的机制增加脂肪细胞数量的可能性，尽管低水平的染料木黄酮通过ER抑制脂肪形成。这增加了高水平的染料木黄酮可以通过非ER介导的机制增加脂肪细胞数量的可能性，尽管低水平的染料木黄酮通过ER抑制脂肪形成。这个建议的中心假设是，新生儿暴露于植物雌激素染料木黄酮将产生重要的剂量依赖性改变脂肪细胞的分化，可能有持久的影响，在成人肥胖，并可能有深远的影响，在成年后期的葡萄糖和胰岛素代谢。为了检验这一假设，将使用涉及向母鼠饮食给予染料木黄酮的生理学相关系统来确定幼鼠中染料木黄酮暴露是否导致脂肪细胞数量、肥胖和/或代谢的成年变化，以及这些影响是否在老年动物中持续存在或加剧。为了分析这种效应的机制基础，我们将确定染料木素暴露诱导分化为脂肪细胞的小鼠胚胎成纤维细胞诱导的基因表达的定量和时间变化，并确定染料木素的作用是否通过ER介导，并涉及PPARgamma和/或细胞周期调节因子p27/kip 1和p21/Cip 1的变化。拟议的研究代表了一个结构化的方法来定义染料木黄酮暴露对脂肪发育的影响及其机制基础。这项工作，沿着其他项目，在这个建议，将寻求评估大豆异黄酮对其他器官系统的影响，他们在衰老过程中发挥的作用，将扩大我们的知识，潜在的人类健康影响的植物雌激素，并允许更明智的决定，在各种情况下，植物雌激素消费的可取性。

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.