Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ

Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ER alpha seems to have a protective role in such diseases, the function of ER beta is not clear. To characterize the metabolic function of ERb, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPAR gamma, in vitro and in high-fat diet (HFD)-fed ER beta -/- mice (beta ERKO) mice. Our in vitro experiments showed that ER beta inhibits ligand-mediated PPAR gamma-transcriptional activity. That resulted in a blockade of PPAR gamma-induced adipocytic gene expression and in decreased adipogenesis. Overexpression of nuclear coactivators such as SRC1 and TIF2 prevented the ER beta-mediated inhibition of PPAR gamma activity. Consistent with the in vitro data, we observed increased PPAR gamma activity in gonadal fat from HFD-fed beta ERKO mice. In consonance with enhanced PPAR gamma activation, HFD-fed beta ERKO mice showed increased body weight gain and fat mass in the presence of improved insulin sensitivity. To directly demonstrate the role of PPAR gamma in HFD-fed beta ERKO mice, PPAR gamma signaling was disrupted by PPAR gamma antisense oligonucleotide (ASO). Blockade of adipose PPAR gamma by ASO reversed the phenotype of beta ERKO mice with an impairment of insulin sensitization and glucose tolerance. Finally, binding of SRC1 and TIF2 to the PPAR gamma-regulated adiponectin promoter was enhanced in gonadal fat from beta ERKO mice indicating that the absence of ER beta in adipose tissue results in exaggerated coactivator binding to a PPAR gamma target promoter. Collectively, our data provide the first evidence that ER beta-deficiency protects against diet-induced IR and glucose intolerance which involves an augmented PPAR gamma signaling in adipose tissue. Moreover, our data suggest that the coactivators SRC1 and TIF2 are involved in this interaction. Impairment of insulin and glucose metabolism by ERb may have significant implications for our understanding of hormone receptor-dependent pathophysiology of metabolic diseases, and may be essential for the development of new ER beta-selective agonists.