Zachary Gerhart-Hines 1 , 2 , Dan Feng 1 , 2 , Matthew J. Emmett 1 , 2 , Logan J. Everett 1 , 2 , Emanuele Loro 4 , 5 , Erika R. Briggs 1 , 2 , Anne Bugge 1 , 2 , Catherine Hou 6 , Christine Ferrara 7 , Patrick Seale 2 , 3 , Daniel A. Pryma 6 , Tejvir S. Khurana 4 , 5 , Mitchell A. Lazar 1 , 2
27 October 2013
Circadian oscillation of body temperature is a basic, evolutionary-conserved feature of mammalian biology 1 . Additionally, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure 2 . 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-erbα, a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare dramatically better at 5 AM (Zeitgeber time 22) when Rev-erbα is barely expressed than at 5 PM (ZT10) when Rev-erbα is abundant. Deletion of Rev-erbα markedly improves cold tolerance at 5 PM, indicating that overcoming Rev-erbα-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 down-regulation of Rev-erbα in BAT. Rev-erbα represses UCP1 in a brown adipose cell-autonomous manner and BAT UCP1 levels are high in Rev-erbα-null mice even at thermoneutrality. Genetic loss of Rev-erbα also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erbα acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands.