Endocrine Abstracts

Nuclear receptor REV-ERBα (NR1D1) is a core component of the molecular circadian clock, a transcription-translation feedback loop which oscillates over 24 hours. REV-ERBα is a constitutive repressor, and we have previously shown that it has extensive, genome-wide binding activity in mouse liver. This repressive function is greatest during the day (inactive period), and is diminished at night. Mice with global deletion of the Rev-erbα gene have a markedly abnormal metabolic phenotype, including heightened adiposity and disordered eating behaviour, and it has been challenging to elucidate the function of REV-ERBα in this model. We have employed a mouse model of inducible, hepatocyte-targeted Rev-erbα deletion, to investigate the role REV-ERBα plays in regulating liver metabolism. We find that the day-night rhythm in respiratory exchange ratio (RER) is altered with liver Rev-erbα deletion, implying an alteration in the day-night rhythm of lipid and carbohydrate utilisation, at a whole animal level. We find that liver REV-ERBα is required to maintain circulating glucose levels during a daytime fast, but not at night. Integration of transcriptome and cistrome datasets suggests that enzymes important for modulating glycogen synthesis and breakdown (Ppp1r3b, Ppp1r3c) are targets of REV-ERBα repression, as is a regulator of pyruvate dehydrogenase activity (Pdk4), which determines whether products of glycolysis or beta-oxidation enter the tricarboxylic acid (TCA) cycle. Taking our findings together, we propose that REV-ERBα exerts rhythmic regulation over critical enzymes involved in energy substrate utilisation. In this manner, REV-ERBα contributes to circadian control of the use of carbohydrate or lipid as fuel, thus playing a key role in the maintenance of energy homeostasis over the day-night cycle.