Publication Date:
2013-10-29
Description:
Circadian oscillation of body temperature is a basic, evolutionarily conserved feature of mammalian biology. In addition, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure. However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown. Here we show that the nuclear receptor Rev-erbalpha (also known as Nr1d1), a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare considerably better at 05:00 (Zeitgeber time 22) when Rev-erbalpha is barely expressed than at 17:00 (Zeitgeber time 10) when Rev-erbalpha is abundant. Deletion of Rev-erbalpha markedly improves cold tolerance at 17:00, indicating that overcoming Rev-erbalpha-dependent repression is a fundamental feature of the thermogenic response to cold. Physiological induction of uncoupling protein 1 (Ucp1) by cold temperatures is preceded by rapid downregulation of Rev-erbalpha in BAT. Rev-erbalpha represses Ucp1 in a brown-adipose-cell-autonomous manner and BAT Ucp1 levels are high in Rev-erbalpha-null mice, even at thermoneutrality. Genetic loss of Rev-erbalpha also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erbalpha acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839416/" 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/PMC3839416/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gerhart-Hines, Zachary -- Feng, Dan -- Emmett, Matthew J -- Everett, Logan J -- Loro, Emanuele -- Briggs, Erika R -- Bugge, Anne -- Hou, Catherine -- Ferrara, Christine -- Seale, Patrick -- Pryma, Daniel A -- Khurana, Tejvir S -- Lazar, Mitchell A -- F-32 DK095563/DK/NIDDK NIH HHS/ -- F32 DK095526/DK/NIDDK NIH HHS/ -- P30 DK019525/DK/NIDDK NIH HHS/ -- P30 DK19525/DK/NIDDK NIH HHS/ -- R01 DK045586/DK/NIDDK NIH HHS/ -- R01 DK45586/DK/NIDDK NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- England -- Nature. 2013 Nov 21;503(7476):410-3. doi: 10.1038/nature12642. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162845" target="_blank"〉PubMed〈/a〉
Keywords:
Acclimatization/genetics/physiology
;
Adipose Tissue, Brown/metabolism
;
Animals
;
Body Temperature Regulation/genetics/*physiology
;
Circadian Rhythm/genetics/*physiology
;
Cold Temperature
;
Down-Regulation
;
Ion Channels/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Mice, Knockout
;
Mitochondrial Proteins/metabolism
;
Nuclear Receptor Subfamily 1, Group D, Member 1/deficiency/genetics/*metabolism
;
Thermogenesis/genetics/physiology
;
Time Factors
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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