ERR alpha: a metabolic function for the oldest orphan

Estrogen receptor related receptor (ERR)alpha was one of the first identified (1988) orphan nuclear receptors. Many of the orphan receptors identified after ERR alpha were deorphanized in a timely manner and appreciated as key transcriptional regulators of metabolic pathways. ERR alpha, however, remains an orphan. Nevertheless, recent studies have defined regulatory mechanisms and transcriptional targets of ERRa, allowing this receptor to join ranks with other nuclear receptors that control metabolism. Notably, mice lacking ERR alpha 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 ERRa for adaptive energy metabolism, and suggest that strategies targeting ERR alpha may be useful in fighting metabolic diseases.