Fiche publication
Date publication
décembre 2015
Journal
Proceedings of the National Academy of Sciences of the United States of America
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
,
Dr MUKHERJI Atish
Tous les auteurs :
Mukherji A, Kobiita A, Chambon P
Lien Pubmed
Résumé
The molecular mechanisms underlying the events through which alterations in diurnal activities impinge on peripheral circadian clocks (PCCs), and reciprocally how the PCCs affect metabolism, thereby generating pathologies, are still poorly understood. Here, we deciphered how switching the diurnal feeding from the active to the rest phase, i.e., restricted feeding (RF), immediately creates a hypoinsulinemia during the active phase, which initiates a metabolic reprogramming by increasing FFA and glucagon levels. In turn, peroxisome proliferator-activated receptor alpha (PPARα) activation by free fatty acid (FFA), and cAMP response element-binding protein (CREB) activation by glucagon, lead to further metabolic alterations during the circadian active phase, as well as to aberrant activation of expression of the PCC components nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbα), Period (Per1 and Per2). Moreover, hypoinsulinemia leads to an increase in glycogen synthase kinase 3β (GSK3β) activity that, through phosphorylation, stabilizes and increases the level of the RevErbα protein during the active phase. This increase then leads to an untimely repression of expression of the genes containing a RORE DNA binding sequence (DBS), including the Bmal1 gene, thereby initiating in RF mice a 12-h PCC shift to which the CREB-mediated activation of Per1, Per2 by glucagon modestly contributes. We also show that the reported corticosterone extraproduction during the RF active phase reflects an adrenal aberrant activation of CREB signaling, which selectively delays the activation of the PPARα-RevErbα axis in muscle and heart and accounts for the retarded shift of their PCCs.
Mots clés
ARNTL Transcription Factors, genetics, Animals, Circadian Clocks, physiology, Cyclic AMP, metabolism, Cyclic AMP Response Element-Binding Protein, metabolism, Fatty Acids, Nonesterified, metabolism, Feeding Behavior, Female, Gene Expression Regulation, Glucagon, metabolism, Homeostasis, Liver, metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscles, metabolism, Mutation, PPAR alpha, metabolism, Period Circadian Proteins, metabolism, Signal Transduction, Time Factors
Référence
Proc. Natl. Acad. Sci. U.S.A.. 2015 Dec;112(48):E6683-90
