期刊
CELL REPORTS
卷 17, 期 4, 页码 1087-1097出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.09.060
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资金
- INSERM
- CNRS
- Ministry of Higher Education and Research
- Hauts de France Regional Council
- European Regional Development Fund (ERDF) through the project Photonics4Society of the Contrat de Plan Etat-Region (CPER) [2015-20120]
- European Genomic Institute for Diabetes (E.G.I.D.) [ANR-10-LABX-46]
- Centre Europeen pour les Mathematiques, la Physique, et leurs Interactions (CEMPI) [ANR-11-LABX-0007]
- European Commission
- European Foundation for the Study of Diabetes (EFSD)
- Fondation Francophone pour la Recherche sur le Diabete (FFRD)
- European Commission EuRhythDia (FP7-health grant) [278397]
- RESOLVE (FP7-health grant) [305707]
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.
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