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      The Nuclear Receptor Rev-erbα Controls Circadian Thermogenic Plasticity

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          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.

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          Most cited references 19

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          The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.

          Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.
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            The genetics of mammalian circadian order and disorder: implications for physiology and disease.

            Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.
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              Regulation of Circadian Behavior and Metabolism by Rev-erbα and Rev-erbβ

              The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERBα and β have been proposed to form an accessory feedback loop that contributes to clock function 1,2 , their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both REV-ERB isoforms, which revealed shared recognition at over 50% of their total sites and extensive overlap with the master circadian regulator BMAL1. While Rev-erbα has been shown to directly regulate Bmal1 expression 1,2 , the cistromic analysis reveals a direct connection between Bmal1 and Rev-erbα and β regulatory circuits than previously suspected. Genes within the intersection of the BMAL1, REV-ERBα and REV-ERBβ cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erbα/β function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data now ally Rev-erbα/β with Per, Cry and other components of the principal feedback loop that drives circadian expression and suggest a more integral mechanism for the coordination of circadian rhythm and metabolism.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                6 November 2013
                27 October 2013
                21 November 2013
                21 May 2014
                : 503
                : 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: (215) 898-0198; lazar@ 123456mail.med.upenn.edu
                Article
                NIHMS523065
                10.1038/nature12642
                3839416
                24162845

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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
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