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

AIM: To investigate the molecular interaction of peroxisome proliferator-activated receptor γ (PPARγ) with 17β-estradiol (E) in the regulation of adipogenesis.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.