ERRα: a metabolic function for the oldest orphan

Abstract

Estrogen receptor related receptor (ERR)α was one of the first identified (1988) orphan nuclear receptors. Many of the orphan receptors identified after ERRα were deorphanized in a timely manner and appreciated as key transcriptional regulators of metabolic pathways. ERRα, however, remains an orphan. Nevertheless, recent studies have defined regulatory mechanisms and transcriptional targets of ERRα, allowing this receptor to join ranks with other nuclear receptors that control metabolism. Notably, mice lacking ERRα show defects when challenged with stressors that require a 'shift of gears' in energy metabolism, such as exposure to cold, cardiac overload or infection. These findings establish the importance of ERRα for adaptive energy metabolism, and suggest that strategies targeting ERRα may be useful in fighting metabolic diseases.

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

“…S3B). As predicted based on studies of ERRα function in other tissues (20,21), gene ontology analysis identified genes broadly involved in metabolic processes ( Fig. S3 C and D).…”

“…Consistent with reduced activation and differentiation of ERRα −/− T cells, stimulation of CD4 + T cells isolated from naive 6-to 8-wk-old ERRα −/− mice resulted in decreased CD44 expression after 24 h (Fig. 1D) and reduced production of IL-2 and IFN-γ ( ERRα associates with the coactivators peroxisome proliferatoractivated receptor-γ coactivator-1α/β (PCG1α/β) to regulate multiple metabolic pathways (20,21) and may link lymphocyte metabolism and function. As CD4 + T cells were also found to express PCG-1β (Fig.…”

“…Because ERRα regulates the transcription of a broad array of metabolic genes (20,21), we examined ERRα expression in CD4 + T lymphocyte metabolism and function. Resting CD4 + T cells expressed ERRα, and although ERRα mRNA expression modestly decreased in CD4 + T cells after 1 d of stimulation (Fig.…”

“…In immunity, ERRα −/− mice exhibit increased susceptibility to Listeria monocytogenes infection (23). Although not previously investigated in lymphocytes, these findings suggest ERRα may regulate genes that contribute to lymphocyte metabolism and activation (20,21).…”

“…The orphan nuclear hormone receptor, estrogen-related receptor-α (ERRα), is associated with poor prognosis (16,17) and tumor growth in breast cancer (18,19). ERRα is also known to regulate cell metabolism (20,21) and Drosophila ERR can promote gene expression to drive carbohydrate metabolism associated with proliferating cells in larval development (22). In immunity, ERRα −/− mice exhibit increased susceptibility to Listeria monocytogenes infection (23).…”