title: Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome.
abstract: The light-entrained master central circadian clock (CC) located in the suprachiasmatic nucleus (SCN) not only controls the diurnal alternance of the active phase (the light period of the human light-dark cycle, but the mouse dark period) and the rest phase (the human dark period, but the mouse light period), but also synchronizes the ubiquitous peripheral CCs (PCCs) with these phases to maintain homeostasis. We recently elucidated in mice the molecular signals through which metabolic alterations induced on an unusual feeding schedule, taking place during the rest phase [i.e., restricted feeding (RF)], creates a 12-h PCC shift. Importantly, a previous study showed that the SCN CC is unaltered during RF, which creates a misalignment between the RF-shifted PCCs and the SCN CC-controlled phases of activity and rest. However, the molecular basis of SCN CC insensitivity to RF and its possible pathological consequences are mostly unknown. Here we deciphered, at the molecular level, how RF creates this misalignment. We demonstrate that the PPARα and glucagon receptors, the two instrumental transducers in the RF-induced shift of PCCs, are not expressed in the SCN, thereby preventing on RF a shift of the master SCN CC and creating the misalignment. Most importantly, this RF-induced misalignment leads to a misexpression (with respect to their normal physiological phase of expression) of numerous CC-controlled homeostatic genes, which in the long term generates in RF mice a number of metabolic pathologies including diabetes, obesity, and metabolic syndrome, which have been reported in humans engaged in shift work schedules.
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;
authors.forename: Manohar
authors.initials: M
authors.lastname: Damara
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964;
authors.forename: Nisha
authors.initials: N
authors.lastname: Misra
authors.affiliation: Institut Clinique de la Souris, Illkirch 67404, France;
authors.forename: Hamid
authors.initials: H
authors.lastname: Meziane
authors.affiliation: Institut Clinique de la Souris, Illkirch 67404, France;
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Champy
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: D000818:Animals; D057906:Circadian Clocks / Q000502:physiology; D002940:Circadian Rhythm; D003920:Diabetes Mellitus / Q000378:metabolism; D004195:Disease Models, Animal; D004435:Eating / Q000502:physiology; D005247:Feeding Behavior; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006937:Hypercholesterolemia / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D056950:Period Circadian Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017440:Photoperiod; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000502:physiology; D013997:Time Factors; D014940:Work Schedule Tolerance
chemical_list: D056950:Period Circadian Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: circadian clocks misalignment; diabetes; metabolic syndrome; mouse; shift work