title: A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function.
abstract: To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting, and a high-fat diet. The model reproduces the dampened clock gene expression and NAD+rhythms reported for mice on a high-fat diet and predicts that this effect may be pharmacologically rescued by timed REV-ERB agonist administration. Our model thus identifies altered AMPK signaling as a mechanism leading to clock disruption and its associated metabolic effects and suggests a pharmacological approach to resetting the clock in obesity.
authors.affiliation: University of Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France; University of Lille, CNRS, UMR 8523-PhLAM-Physique des Lasers, Atomes et Molécules, 59000 Lille, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Woller
authors.affiliation: University of Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Duez
authors.affiliation: University of Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France. Electronic address: bart.staels@pasteur-lille.fr.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: University of Lille, CNRS, UMR 8523-PhLAM-Physique des Lasers, Atomes et Molécules, 59000 Lille, France. Electronic address: marc.lefranc@univ-lille1.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Lefranc
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005215:Fasting / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008099:Liver / Q000502:physiology*; D018345:Mice, Knockout; D008820:Mice, Obese; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000819:agonists / Q000378:metabolism; D010641:Phenotype; D056564:Sirtuin 1 / Q000378:metabolism; D013997:Time Factors
chemical_list: C538964:Cry1 protein, mouse; D056931:Cryptochromes; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D009243:NAD; D000249:Adenosine Monophosphate; D000263:Adenylate Kinase; D056564:Sirtuin 1
keywords: AMPK; NAD(+); NAMPT; REV-ERB; SIRT1; mammalian circadian clock; mathematical model; metabolic disorders; metabolism