Emerging Roles of Estrogen-Related Receptors in the Brain: Potential Interactions with Estrogen Signaling

Abstract

In addition to their well-known role in the female reproductive system, estrogens can act in the brain to regulate a wide range of behaviors and physiological functions in both sexes. Over the past few decades, genetically modified animal models have greatly increased our knowledge about the roles of estrogen receptor (ER) signaling in the brain in behavioral and physiological regulations. However, less attention has been paid to the estrogen-related receptors (ERRs), the members of orphan nuclear receptors whose sequences are homologous to ERs but lack estrogen-binding ability. While endogenous ligands of ERRs remain to be determined, they seemingly share transcriptional targets with ERs and their expression can be directly regulated by ERs through the estrogen-response element embedded within the regulatory region of the genes encoding ERRs. Despite the broad expression of ERRs in the brain, we have just begun to understand the fundamental roles they play at molecular, cellular, and circuit levels. Here, we review recent research advancement in understanding the roles of ERs and ERRs in the brain, with particular emphasis on ERRs, and discuss possible cross-talk between ERs and ERRs in behavioral and physiological regulations.

Keywords: brain; central nervous system; estrogen; estrogen receptor; estrogen-related receptors; mitochondria.

Figure 1

Schematic drawing showing potential cross-talk between estrogen, estrogen receptors (ERs), and estrogen-related receptors (ERRs). Dotted lines indicate relatively weak binding ability. MHRE, multiple-hormone response element; CYP19, aromatase.

Figure 2

Representative immunohistochemistry (IHC) images showing ERRα (A) and ERα (B) expression in the mouse brain. Digital zooms of individual boxed regions are shown in A1, A2, B1, and B2. Note that expression pattern of ERRα and ERα is similar in the cortex and the hippocampus (A1,B1), but strikingly different expression was observed in the mediobasal hypothalamus (A2,B2) that is critical for the homeostatic regulation of energy balance. Note: the IHC image shown in (A) was from our previous publication with a zoom-in view [81]. The IHC image shown in (B) was from the brain sections of an adult female wild-type mouse stained with validated commercially available ERα antibody (1:1000, Millipore) as reported previously [71]. This ERα antibody was validated in conditional ERα KO mice previously [68]. Scale bar = 1 mm in A and B, and 500 µm in A1, A2, B1, and B2.

Figure 3

ERs and ERRs regulate a variety of important cellular functions and any disruption in these processes can lead to different pathological conditions. MitoBio, mitochondrial biogenesis; β-OX, beta-oxidation; FAO, fatty acid oxidation; Oxphos, oxidative phosphorylation; ETC, electron transport chain. Red dot indicates estrogens and “?” indicates unknown ligands for ERRs.