Publication Date:
2012-03-31
Description:
Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-alpha and REV-ERB-beta 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343186/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343186/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solt, Laura A -- Wang, Yongjun -- Banerjee, Subhashis -- Hughes, Travis -- Kojetin, Douglas J -- Lundasen, Thomas -- Shin, Youseung -- Liu, Jin -- Cameron, Michael D -- Noel, Romain -- Yoo, Seung-Hee -- Takahashi, Joseph S -- Butler, Andrew A -- Kamenecka, Theodore M -- Burris, Thomas P -- DK080201/DK/NIDDK NIH HHS/ -- DK088499/DK/NIDDK NIH HHS/ -- DK089984/DK/NIDDK NIH HHS/ -- MH092769/MH/NIMH NIH HHS/ -- R01 DK073189/DK/NIDDK NIH HHS/ -- R01 DK080201/DK/NIDDK NIH HHS/ -- R01 DK080201-05/DK/NIDDK NIH HHS/ -- R01 MH092769/MH/NIMH NIH HHS/ -- R01 MH092769-02/MH/NIMH NIH HHS/ -- R01 MH093429/MH/NIMH NIH HHS/ -- R01 MH093429-01A1/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 29;485(7396):62-8. doi: 10.1038/nature11030.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460951" target="_blank"〉PubMed〈/a〉
Keywords:
Adipose Tissue/drug effects/metabolism
;
Animals
;
Biological Clocks/drug effects/genetics/physiology
;
Circadian Rhythm/*drug effects/genetics/*physiology
;
Disease Models, Animal
;
Energy Metabolism/*drug effects
;
HEK293 Cells
;
Humans
;
Hypothalamus/drug effects/metabolism
;
Liver/drug effects/metabolism
;
Metabolome/drug effects
;
Mice
;
Mice, Inbred BALB C
;
Mice, Inbred C57BL
;
Muscle, Skeletal/drug effects/metabolism
;
Nuclear Receptor Subfamily 1, Group D, Member 1/*antagonists &
;
inhibitors/metabolism
;
Obesity/chemically induced/drug therapy/metabolism
;
Pyrrolidines/*pharmacology
;
Receptors, Cytoplasmic and Nuclear/*antagonists & inhibitors/metabolism
;
Repressor Proteins/*antagonists & inhibitors/metabolism
;
Thiophenes/*pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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