REV-ERB nuclear receptors in the suprachiasmatic nucleus control circadian period and restrict diet-induced obesity

Circadian disruption, as shift work, is associated with metabolic diseases, including obesity and fatty liver, often attributed to discordance between internal clocks and environmental timekeepers1-5. However, this desynchrony hypothesis has not been rigorously tested. The body’s master clock, located in the suprachiasmatic nucleus (SCN), synchronizes peripheral clocks and ultimately metabolism2,6. Molecular clocks are comprised of transcriptional translational feedback loops involving gene activation by BMAL1, which is rhythmically repressed by separate mechanisms involving PER/CRY and REV-ERB nuclear receptors. Mice harboring whole body deletion of REV-ERBa/b have been reported to be arrhythmic7. However, we report here that mice lacking REV-ERBs specifically in the SCN maintain free-running and metabolic rhythms, but these are strikingly shortened by nearly 3 hours. When housed under a 24 hours light-dark cycle and fed an obesogenic diet, these mice gained excess weight and accrued more liver fat than controls. Remarkably, these metabolic disturbances were corrected by matching environmental lighting to the shortened endogenous clock period. Thus, SCN REV-ERBs are not required to maintain rhythmicity but powerfully control the free-running period. Moreover, these results support the hypothesis that dissonance between environmental conditions and endogenous period causes metabolic disruption. This has important implications for chronotherapy of metabolic and behavioral disorders. Transcriptomic profiling (RNA-seq) of punched-out suprachiasmatic nuclei (SCN) harvested from control or REV-ERBS (alpha and beta) DKKO mice collected during at CT4 or CT16. Library was prepared with Illumina Truseq kit and sequenced on Illumina Hiseq 4000 sequencer.