Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists

Laura A. Solt, Yongjun Wang, Subhashis Banerjee, Travis Hughes, Douglas J. Kojetin, Thomas Lundasen, Youseung Shin, Jin Liu, Michael D. Cameron, Romain Noel, Seung-Hee Yoo, Joseph S. Takahashi, Andrew A. Butler, Theodore M. Kamenecka and Thomas P. Burris ()
Additional contact information
Laura A. Solt: The Scripps Research Institute
Yongjun Wang: The Scripps Research Institute
Subhashis Banerjee: The Scripps Research Institute
Travis Hughes: The Scripps Research Institute
Douglas J. Kojetin: The Scripps Research Institute
Thomas Lundasen: The Scripps Research Institute
Youseung Shin: Translational Research Institute, The Scripps Research Institute
Jin Liu: The Scripps Research Institute
Michael D. Cameron: Translational Research Institute, The Scripps Research Institute
Romain Noel: Translational Research Institute, The Scripps Research Institute
Seung-Hee Yoo: University of Texas Southwestern Medical Center
Joseph S. Takahashi: University of Texas Southwestern Medical Center
Andrew A. Butler: The Scripps Research Institute
Theodore M. Kamenecka: Translational Research Institute, The Scripps Research Institute
Thomas P. Burris: The Scripps Research Institute

Nature, 2012, vol. 485, issue 7396, 62-68

Abstract: Abstract Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.

Date: 2012
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DOI: 10.1038/nature11030

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