AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation
Open accessAbstract
Circadian clocks coordinate behavioral and physiological processes with daily light-dark cycles by driving rhythmic transcription of thousands of genes. Whereas the master clock in the brain is set by light, pacemakers in peripheral organs, such as the liver, are reset by food availability, although the setting, or "entrainment," mechanisms remain mysterious. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.
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CRY1 and CRY2, implicated in the ADHD-associated dysregulation of the circadian system, are modelled through AMPK activity by MPH improving the impairment of this system.
“These CLOCK components CRY1 and CRY2, implicated in the ADHD-associated dysregulation of the circadian system [213], are modelled through AMPK activity by MPH improving the impairment of this system [214].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [213]
The passage labelled Abstract (page unavailable) reports that AMPK phosphorylates and destabilizes CRY1 and that AMPK stimulation alters circadian rhythms in mouse fibroblasts and livers. It does not show that MPH acts through AMPK or improves circadian impairment; the passages found also do not establish the specific CRY2 mechanism. The ADHD association is attached to citation [213], not this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredActivation of AMPK leads to altered circadian rhythms by destabilizing the negative limb of the circadian clock.
“Indeed, activation of adenosine monophosphate-activated protein kinase (AMPK), a sensor of low intracellular energy and nutrient state, leads to altered circadian rhythms by destabilizing the negative limb of the circadian clock [41,42].”
From Circadian control of glucose metabolism (2014) · cites this paper as [42]
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- Authors
- Lamia, K. A., Sachdeva, U. M., DiTacchio, L., Williams, E. C., Alvarez, J. G., Egan, D. F., Vasquez, D. S., Juguilon, H., Panda, S., Shaw, R. J., Thompson, C. B., & Evans, R. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Abramson Cancer Center (US)
- Corresponding author
- Lamia, Katja A.
- Sachdeva, Uma M.
- Thompson, Craig B.
- Evans, Ronald M.
- ORCID
- Venue
- Science
- Published
- 2009-10-16
- Volume
- 326
- Issue
- 5951
- Pages
- 437-440
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2819106
- OpenAlex
- W2004849589
- Cited by
- 958
- References
- 29
- Citations by year
- 2026: 42 · 2025: 57 · 2024: 48 · 2023: 55 · 2022: 55 · 2021: 64 · 2020: 76 · 2019: 54 · 2018: 49 · 2017: 59 · 2016: 73 · 2015: 55 · 2014: 54 · 2013: 62 · 2012: 61
- FWCI
- 22.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (T32-HL07439-27, T32HL007439)
- National Eye Institute (R01EY016807, EY016807)
- National Cancer Institute (P01CA104838, CA104838, P30CA014195)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, DK080425, DK057978, DK062434, R01DK080425, U19DK062434)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
- Keywords
- AMPK, circadian clock, CRY1, protein degradation, nutrient signaling, peripheral clocks, clock entrainment, liver, mouse fibroblasts
- MeSH terms
- Aminoimidazole Carboxamide, Animals, Cell Line, Cell Nucleus, Cells, Cultured, Circadian Rhythm, Culture Media, Flavoproteins, Food, Glucose, Humans, Liver, Phosphorylation, Promoter Regions, Genetic, Recombinant Fusion Proteins, Ribonucleotides, Signal Transduction, Mutagenesis, Site-Directed, Amino Acid Substitution, Mutant Proteins, Mice, Basic Helix-Loop-Helix Proteins, AMP-Activated Protein Kinases, Protein Stability, ARNTL Transcription Factors, Cryptochromes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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