Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function
- Anne Bugge,
- Dan Feng,
- Logan J. Everett,
- Erika R. Briggs,
- Shannon E. Mullican,
- Fenfen Wang,
- Jennifer Jager and
- Mitchell A. Lazar1
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Abstract
The nuclear receptor Rev-erbα regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erbα together with closely related Rev-erbβ has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.
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Footnotes
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↵1 Corresponding author.
E-mail lazar{at}mail.med.upenn.edu.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.186858.112.
- Received January 10, 2012.
- Accepted March 1, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press