Letter | Published:

The nuclear receptor Rev-erbα controls circadian thermogenic plasticity

Nature volume 503, pages 410413 (21 November 2013) | Download Citation

Abstract

Circadian oscillation of body temperature is a basic, evolutionarily conserved feature of mammalian biology1. In addition, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure2. 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 (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-erbα is barely expressed than at 17:00 (Zeitgeber time 10) when Rev-erbα is abundant. Deletion of Rev-erbα markedly improves cold tolerance at 17:00, 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 downregulation 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.

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Acknowledgements

We thank the Functional Genomics Core (J. Schug) and the Mouse Phenotyping, Physiology, and Metabolism Core (R. Ahima and R. Dhir) of the Penn Diabetes Research Center (NIH P30 DK19525). We also thank the Small Animal Imaging Facility of the Perelman School of Medicine at the University of Pennsylvania (E. Blankemeyer). This work was supported by NIH grants R01 DK45586 (M.A.L.) and F-32 DK095563 (Z.G.-H.) and the JPB Foundation. A.B. was funded by the Novo Nordisk STAR postdoctoral program.

Author information

Author notes

    • Dan Feng
    •  & Matthew J. Emmett

    These authors contributed equally to this work.

Affiliations

  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

    • Zachary Gerhart-Hines
    • , Dan Feng
    • , Matthew J. Emmett
    • , Logan J. Everett
    • , Erika R. Briggs
    • , Anne Bugge
    •  & Mitchell A. Lazar
  2. The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Zachary Gerhart-Hines
    • , Dan Feng
    • , Matthew J. Emmett
    • , Logan J. Everett
    • , Erika R. Briggs
    • , Anne Bugge
    • , Patrick Seale
    •  & Mitchell A. Lazar
  3. Department of Physiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Emanuele Loro
    •  & Tejvir S. Khurana
  4. Pennsylvania Muscle Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Emanuele Loro
    •  & Tejvir S. Khurana
  5. Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Catherine Hou
    •  & Daniel A. Pryma
  6. Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA

    • Christine Ferrara
  7. Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Patrick Seale

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Contributions

D.F., M.J.E., L.J.E., E.R.B., A.B. and C.F. performed key experiments/data analysis and read the manuscript. P.S. provided advice and read the manuscript. E.L. and T.S.K. designed, performed and analysed EMG studies and read the manuscript. C.H. and D.A.P. designed, performed and analysed 18FDG scans and read the manuscript. Z.G.H. performed many of the experiments, and Z.G.H. and M.A.L. conceived the project, designed experiments, analysed all results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mitchell A. Lazar.

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DOI

https://doi.org/10.1038/nature12642

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