The circadian REV-ERB nuclear receptors are essential drivers of heart metabolism and function

The heart is a highly metabolic organ that uses multiple energy sources to meet its demand for ATP production. Diurnal feeding-fasting cycles result in substrate availability fluctuations which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBa and b are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, we generated mice with cardiomyocyte (CM)-specific deletion of both Rev-erbs, which died prematurely due to dilated cardiomyopathy. Loss of Rev-erbs markedly downregulated fatty acid oxidation genes prior to overt pathology, which was mediated by induction of the transcriptional repressor E4BP4, a direct target of cardiac REV-ERBs. E4BP4 directly controls circadian expression of Nampt and its biosynthetic product NAD+ via distal cis-regulatory elements. Thus, REV-ERB-mediated E4BP4 repression is required for Nampt expression and NAD+ production by the salvage pathway. Together, these results highlight the indispensable role of circadian REV-ERBs in cardiac gene expression, metabolic homeostasis and function. RNA-Sequencing was performed on 2-months-old control versus CM-RevDKO hearts, that were harvested at ZT10. H3K27ac Cut&Run was performed on isolated adult cardiomyocytes from control versus CM-RevDKO mice at ZT10. ChIP-Seq for HA-Rev-erba and E4BP4 was performed on biventricles of male mouse hearts (age 2 months), harvested at ZT10.