The Nuclear Receptor Rev-erbα Controls Circadian Thermogenic Plasticity

Abstract

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.

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 6 November 2013

Publication date (Electronic): 27 October 2013

Publication date (Print): 21 November 2013

Publication date PMC-release: 21 May 2014

Volume: 503

Issue: 7476

Affiliations

[1 ]Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA

[2 ]The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA

[3 ]Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA

[4 ]Department of Physiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA

[5 ]Pennsylvania Muscle Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA

[6 ]Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA

[7 ]Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA

Author notes

Address correspondence and requests for materials to: Mitchell A. Lazar, M.D., Ph.D., Phone: [phone]; lazar@ 123456mail.med.upenn.edu

Article

Manuscript ID: NIHMS523065

DOI: 10.1038/nature12642

PMC ID: 3839416

PubMed ID: 24162845

License:

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Funding

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

Award ID: R01 DK045586 || DK

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

Award ID: P30 DK019525 || DK

Categories

Subject: Article