title: Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours.
abstract: 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964;
authors.forename: Atish
authors.initials: A
authors.lastname: Mukherji
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964;
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kobiita
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964; University of Strasbourg Institute for Advanced Study, Collège de France, Illkirch 67404, France chambon@igbmc.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D057906:Circadian Clocks / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005247:Feeding Behavior; D005260:Female; D005786:Gene Expression Regulation; D005934:Glucagon / Q000378:metabolism; D006706:Homeostasis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D047493:PPAR alpha / Q000378:metabolism; D056950:Period Circadian Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005230:Fatty Acids, Nonesterified; D047493:PPAR alpha; D056950:Period Circadian Proteins; D005934:Glucagon; D000242:Cyclic AMP
keywords: PPARα; RevErbα; metabolic alterations; shifted eating; shifted peripheral circadian clocks