title: Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists.
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.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Subhashis
authors.initials: S
authors.lastname: Banerjee
authors.forename: Travis
authors.initials: T
authors.lastname: Hughes
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kojetin
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundasen
authors.forename: Youseung
authors.initials: Y
authors.lastname: Shin
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Romain
authors.initials: R
authors.lastname: Noel
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoo
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Butler
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D055442:Metabolome / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C498262:Nr1d1 protein, mouse; C499650:Nr1d2 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011759:Pyrrolidines; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C572451:SR9009; C572450:SR9011; D013876:Thiophenes