Nuclear receptor Rev-erbα: up, down, and all around

•Rev-erbα is an unusual nuclear receptor that is dedicated to transcriptional repression. •NCoR and HDAC3 are important and functional corepressor partners of Rev-erbα. •Rev-erbα is a key component of a core repressive loop of the molecular clock. •Rev-erbα is a circadian regulator of metabolic pathways in multiple tissues. Rev-erbα is a nuclear receptor that links circadian rhythms to transcriptional control of metabolic pathways. Rev-erbα is a potent transcriptional repressor and plays an important role in the core mammalian molecular clock while also serving as a key regulator of clock output in metabolic tissues including liver and brown adipose tissue (BAT). Recent findings have shed new light on the role of Rev-erbα and its paralog Rev-erbβ in rhythm generation, as well as additional regulatory roles for Rev-erbα in other tissues that contribute to energy expenditure, inflammation, and behavior. This review highlights physiological functions of Rev-erbα and β in multiple tissues and discusses the therapeutic potential and challenges of targeting these pathways in human disease. Rev-erbα is a nuclear receptor that links circadian rhythms to transcriptional control of metabolic pathways. Rev-erbα is a potent transcriptional repressor and plays an important role in the core mammalian molecular clock while also serving as a key regulator of clock output in metabolic tissues including liver and brown adipose tissue (BAT). Recent findings have shed new light on the role of Rev-erbα and its paralog Rev-erbβ in rhythm generation, as well as additional regulatory roles for Rev-erbα in other tissues that contribute to energy expenditure, inflammation, and behavior. This review highlights physiological functions of Rev-erbα and β in multiple tissues and discusses the therapeutic potential and challenges of targeting these pathways in human disease.