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

Abstract

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

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

“…Treatment of a nuclear extract with troglitazone increased PPARγ-binding activity, but E interfered with the troglitazone-induced DNA binding of PPARγ. Similarly, other research has shown that E and E-like compounds inhibited the DNA-binding activity of PPARγ and that nuclear extracts isolated from adipose tissues of ERβ-KO mice showed increased binding of endogenous PPARγ in comparison with wild-type mice [26] . PPARγ-binding activity was also markedly decreased in the phytoestrogen genistein-treated cells compared with untreated control [39] .…”

“…Thus, these data indicate that E inhibits PPARγ-dependent transactivation through ERs. Recently, Foryst-Ludwig et al also reported that ERβ inhibited ligand-mediated PPARγ transcriptional activity in 3T3-L1 preadipocytes transfected with PPARγ [26] . In contrast to our results, these authors found that pioglitazone-stimulated PPARγ activity was not blocked by ERα.…”

“…Transcriptional stimulation and suppression, in response to ligand binding to PPARγ or ERs, are mediated by interactions with coactivator proteins, such as steroid receptor coactivator-1 (SRC-1) and CREB-binding protein (CBP), and corepressor proteins, such as nuclear receptor CoR (a silencing mediator of retinoic acid) and thyroid hormone receptor. It has previously been shown that competition between nuclear receptors for coactivator binding results in a negative cross-talk between nuclear receptors [25,26] .…”

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

“…Recently, it has been demonstrated that ER is important for adiposity regulation when mice are challenged with a high fat diet (Foryst-Ludwig et al, 2008). LXRs are well recognized as important regulators of cholesterol homeostasis as well as modulators of lipid and carbohydrate metabolism.…”

“…Recently, it has been demonstrated that ER is important for adiposity regulation when mice are challenged with a high fat diet (Foryst-Ludwig et al, 2008). et al, 2003).…”