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Reciprocal Regulation of Brain and Muscle Arnt-Like Protein 1 and Peroxisome Proliferator-Activated Receptor Defines a Novel Positive Feedback Loop in the Rodent Liver Circadian Clock

Structure and Evolution of Nuclear Receptors (L.C., J.R., V.L.), Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 5161, Institut Fédératif de Recherche (IFR) 128 BioSciences Lyon-Gerland, Laboratoire de Biologie Moléculaire de la Cellule, Ecole Normale Supérieure, 69364 Lyon cedex 07, France; Institut National de la Santé et de la Recherche Médicale Unité 371 (O.D.-B.), Laboratoire Cerveau et Vision, IFR 19-Université Claude Bernard Lyon 1, 69675 Bron, France; Université de Nice Sophia Antipolis CNRS Formation de Recherche en Evolution (B.R., F.D.), 06108 Nice cedex 2, France; and Center for Integrative Genomics (N.S.T., L.M., W.W.), University of Lausanne, CH-1015 Lausanne, Switzerland

Address all correspondence and requests for reprints to: Vincent Laudet, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5161, Institut Fédératif de Recherche 128 BioSciences Lyon-Gerland, Laboratoire de Biologie Moléculaire de la Cellule, Ecole Normale Supérieure, 46 allée d’Italie, 69364 Lyon cedex 07, France. E-mail: vincent.laudet{at}ens_lyon.fr.

Recent evidence has emerged that peroxisome proliferator-activated receptor (PPAR), which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPAR influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPAR plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPAR on a potential PPAR response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPAR gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPAR in peripheral clocks.

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Nuclear Receptors:   PPARα  |  REV-ERBα

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