Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac 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 fluctuations in substrate availability, which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and REV-ERBβ are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, here we generated mice with cardiomyocyte (CM)-specific deletion of both Rev-erb genes (Nr1d1/2), which died prematurely due to dilated cardiomyopathy. Loss of REV-ERBs markedly downregulated expression of fatty acid-oxidation genes before 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. Sustained cardiac function depends on circadian REV-ERBs. Here, Dierickx et al. show that circadian nuclear receptors REV-ERBα and β are indispensable to establish the transcriptional program that controls cardiac metabolism and NAD+ production. Deregulation of REV-ERBs leads to dilated cardiomyopathy and premature death.