ERbeta is a negative regulator of the PPARgamma in vivo

Aims: The estrogen receptors (ERs) and the peroxisome proliferator-activated receptor gamma (PPARgamma) are members of the nuclear hormone receptor family (NHR) which act as eukaryotic ligand-dependent transcription factors. The molecular mechanisms underlying PPARgamma function are similar to those of ER-signaling. Importantly, PPARgamma is sharing an identical pool of nuclear cofactors with ERbeta which provides a platform for mutual interactions between these two NHRs. The PPARgamma is a major regulator of glucose and lipid metabolism. Furthermore PPARgamma was shown to be also a key player in arteriosclerosis and cardiovascular diseases, as its role expands beyond its primary action in adipose tissue, and involves the regulation of adipocytokine production such as adiponectin.

Results: To determine the functional significance of ERbeta in cardiovascular and metabolic diseases in vivo we undertook studies in bERKO mice. When set on high fat diet (59% kcal from fat for 12 weeks) female bERKO mice show higher endogenous PPARgamma activity in gonadal fat tissue in comparison to wild-type (WT) control mice in EMSA assay. Moreover bERKO mice have increased PPARgamma-target gene expression in gonadal fat (wt vs. bERKO) including lipoprotein lipase lpl (1, 48±0,1 vs. 4,3±0,35) and adiponectin (0,92±0,14 vs. 1,42±0,28). Consistently with these findings, adiponectin serum level was significantly elevated in bERKO mice. To investigate the mechanism of increased adiponectin expression in vivo, we performed Chromatin IP experiments in gonadal fat from HFD-fed bERKO and wt mice. PPARgamma binding to the adiponectin promoter was present in both gonadal adipose tissues isolated from bERKO and wt-mice. However, binding of the coactivators SRC1 and TIF2 was enhanced in gonadal fat from bERKO mice, indicating that the absence of ERbeta in adipose tissue results in exaggerated coactivator binding to a PPARgamma target promoter.

Conclusions: Together these data suggest that the coactivators SRC1 and TIF2 are involved in the negative regulation of PPARgamma by ERbeta in-vivo. Molecular interactions between ERs and PPARs may help to understand the function of sex nuclear hormone receptors in cardiovascular and metabolic diseases.