Department of Life Sciences, Mokwon University, Daejeon, Korea.
Acta Pharmacol Sin. 2011 Feb;32(2):230-8. doi: 10.1038/aps.2010.198.
To investigate the molecular interaction of peroxisome proliferator-activated receptor γ (PPARγ) with 17β-estradiol (E) in the regulation of adipogenesis.
Female ovariectomized (OVX) mice and differentiated 3T3-L1 adipocytes were treated with combinations of the PPARγ agonist troglitazone or E, and the variables and determinants of adipogenesis were measured using in vivo and in vitro approaches.
Troglitazone (250 mg·kg(-1)·d(-1) for 13 weeks) decreased the size of adipocytes without the change in white adipose tissue (WAT) mass and increased the expression of adipocyte-specific genes, such as PPARγ, adipocyte fatty acid binding protein, and lipoprotein lipase, compared with OVX control mice. E (0.05 mg/pellet, sc implanted) significantly reduced WAT mass, adipocyte size, and adipose marker gene expression. When mice were concomitantly treated with troglitazone and E, E blunted the effects of troglitazone on WAT mass, adipocyte size, and adipose PPARγ target gene expression. Consistent with the in vivo data, E (10 μmol/L) treatment inhibited lipid accumulation and the expression of adipocyte-specific genes caused by troglitazone (10 μmol/L) in 3T3-L1 cells. E (10 μmol/L) also decreased troglitazone-induced PPARγ reporter activity through both estrogen receptor (ER) α and ERβ. Mechanistic studies indicated that E (0.1 μmol/L) decreased the DNA binding of PPARγ induced by troglitazone (1 μmol/L) and inhibited the recruitment of the PPARγ coactivator CREB-binding protein.
These results suggest that in vivo and in vitro treatment of E interferes with the actions of PPARγ on adipogenesis by down-regulating adipogenesis-related genes, which are mediated through the inhibition of PPARγ coactivator recruitment. In addition, it is likely that the activities of PPARγ activators may be enhanced in estrogen-deficient states.
研究过氧化物酶体增殖物激活受体γ（PPARγ）与 17β-雌二醇（E）在调节脂肪生成中的分子相互作用。
用 PPARγ 激动剂曲格列酮或 E 处理雌性去卵巢（OVX）小鼠和分化的 3T3-L1 脂肪细胞，并采用体内和体外方法测量脂肪生成的变量和决定因素。
与 OVX 对照组小鼠相比，曲格列酮（250mg·kg(-1)·d(-1)，治疗 13 周）降低了脂肪细胞的大小，而不改变白色脂肪组织（WAT）的质量，并增加了脂肪细胞特异性基因的表达，如 PPARγ、脂肪细胞脂肪酸结合蛋白和脂蛋白脂肪酶。E（0.05mg/丸，sc 植入）可显著降低 WAT 质量、脂肪细胞大小和脂肪标记基因表达。当小鼠同时接受曲格列酮和 E 治疗时，E 减弱了曲格列酮对 WAT 质量、脂肪细胞大小和脂肪组织中 PPARγ 靶基因表达的影响。与体内数据一致，E（10μmol/L）抑制了曲格列酮（10μmol/L）引起的 3T3-L1 细胞中脂肪积累和脂肪细胞特异性基因的表达。E（10μmol/L）还通过雌激素受体（ER）α和 ERβ 降低了曲格列酮诱导的 PPARγ 报告基因活性。机制研究表明，E（0.1μmol/L）降低了曲格列酮（1μmol/L）诱导的 PPARγ 的 DNA 结合，并抑制了 PPARγ 共激活因子 CREB 结合蛋白的募集。
这些结果表明，体内和体外 E 处理通过下调与脂肪生成相关的基因来干扰 PPARγ 对脂肪生成的作用，这是通过抑制 PPARγ 共激活因子募集来介导的。此外，在雌激素缺乏状态下，PPARγ 激活剂的活性可能增强。
