Activation of 5′-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase Iɛ (CKIɛ)-dependent Degradation of Clock Protein mPer2
Open accessAbstract
Metformin is one of the most commonly used first line drugs for type II diabetes. Metformin lowers serum glucose levels by activating 5'-AMP-activated kinase (AMPK), which maintains energy homeostasis by directly sensing the AMP/ATP ratio. AMPK plays a central role in food intake and energy metabolism through its activities in central nervous system and peripheral tissues. Since food intake and energy metabolism is synchronized to the light-dark (LD) cycle of the environment, we investigated the possibility that AMPK may affect circadian rhythm. We discovered that the circadian period of Rat-1 fibroblasts treated with metformin was shortened by 1 h. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2. In peripheral tissues, injection of metformin leads to mPer2 degradation and a phase advance in the circadian expression pattern of clock genes in wild-type mice but not in AMPK alpha2 knock-out mice. We conclude that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Activation 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 [41]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652 · see citing works
Coordination of circadian timing in mammals
Reppert, S. M., & Weaver, D. R. (2002) · Nature · doi:10.1038/nature00965 · Cited by 4,379 · see citing works
Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799 · see citing works
Entrainment of the circadian clock in the liver by feeding
Stokkan, K.-A., Yamazaki, S., Tei, H., Sakaki, Y., & Menaker, M. (2001) · Science · doi:10.1126/science.291.5503.490 · Cited by 1,800 · see citing works
Self-citationAMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus
Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferré, P., Birnbaum, M. J., et al. (2004) · Nature · doi:10.1038/nature02440 · Cited by 1,637 · see citing works
Hawley, S. A., Davison, M., Woods, A., Davies, S. P., Beri, R. K., Carling, D., & Hardie, D. G. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.44.27879 · Cited by 1,264 · see citing works
Positional Syntenic Cloning and Functional Characterization of the Mammalian Circadian Mutation tau
Lowrey, P. L., Shimomura, K., Antoch, M. P., Yamazaki, S., Zemenides, P. D., Ralph, M. R., Menaker, M., & Takahashi, J. S. (2000) · Science · doi:10.1126/science.288.5465.483 · Cited by 860 · see citing works
Self-citationMammalian AMP-activated protein kinase subfamily
Stapleton, D., Mitchelhill, K. I., Gao, G., Widmer, J., Michell, B. J., Teh, T., House, C. M., Fernandez, C. S., Cox, T., Witters, L. A., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.2.611 · Cited by 652 · see citing works
Carling, D., Zammit, V. A., & Hardie, D. G. (1987) · FEBS Letters · doi:10.1016/0014-5793(87)80292-2 · Cited by 599 · see citing works
Jørgensen, S. B., Viollet, B., Andreelli, F., Frøsig, C., Birk, J. B., Schjerling, P., Vaulont, S., Richter, E. A., & Wojtaszewski, J. F. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306205200 · Cited by 553 · see citing works
Self-citationThe AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity
Viollet, B., Andreelli, F., Jørgensen, S. B., Perrin, C., Geloen, A., Flamez, D., Mu, J., Lenzner, C., Baud, O., Bennoun, M., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16567 · Cited by 499 · see citing works
Self-citationControl of Mammalian Circadian Rhythm by CKIε-Regulated Proteasome-Mediated PER2 Degradation
Eide, E. J., Woolf, M. F., Kang, H., Woolf, P., Hurst, W., Camacho, F., Vielhaber, E. L., Giovanni, A., & Virshup, D. M. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.7.2795-2807.2005 · Cited by 495 · see citing works
Self-citationSullivan, J. E., Brocklehurst, K. J., Marley, A. E., Carey, F., Carling, D., & Beri, R. K. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)01006-4 · Cited by 488 · see citing works
Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts
Balsalobre, A., Marcacci, L., & Schibler, U. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00758-2 · Cited by 485 · see citing works
Laderoute, K. R., Amin, K., Calaoagan, J. M., Knapp, M., Le, T., Orduna, J. M., Foretz, M., & Viollet, B. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00166-06 · Cited by 443 · see citing works
Self-citationNuclear Entry of the Circadian Regulator mPER1 Is Controlled by Mammalian Casein Kinase I ɛ
Vielhaber, E. L., Eide, E. J., Rivers, A. M., Gao, Z.-H., & Virshup, D. M. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.13.4888-4899.2000 · Cited by 308 · see citing works
A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo
Yoo, S. H., Ko, C. H., Lowrey, P. L., Buhr, E. D., Song, E.-J., Chang, S., Yoo, O. J., Yamazaki, S., Lee, C., & Takahashi, J. S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409763102 · Cited by 299 · see citing works
Self-citationReal-time luminescence reporting of circadian gene expression in mammals
Yamazaki, S., & Takahashi, J. S. (2005) · Methods in Enzymology · doi:10.1016/s0076-6879(05)93012-7 · Cited by 200 · see citing works
Self-citationAn opposite role for tau in circadian rhythms revealed by mathematical modeling
Gallego, M., Eide, E. J., Woolf, M. F., Virshup, D. M., & Forger, D. B. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604511103 · Cited by 176 · see citing works
Gietzen, K. F., Cegielska, A., Getman, M. E., Landes, G. M., & Virshup, D. M. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.25.14875 · Cited by 167 · see citing works
Izumo, M., Johnson, C. H., & Yamazaki, S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2536313100 · Cited by 161 · see citing works
Self-citationHuman casein kinase Iδ phosphorylation of human circadian clock proteins period 1 and 2
Camacho, F., Cilio, M., Guo, Y., Virshup, D. M., Patel, K., Khorkova, O., Styren, S. D., Morse, B., Yao, Z., & Keesler, G. A. (2001) · FEBS Letters · doi:10.1016/s0014-5793(00)02434-0 · Cited by 153 · see citing works
Phosphorylation and destabilization of human period I clock protein by human casein kinase Iε
Keesler, G. A., Camacho, F., Guo, Y. X., Virshup, D. M., Mondadori, C., & Yao, Z. (2000) · Neuroreport · doi:10.1097/00001756-200004070-00011 · Cited by 136 · see citing works
Gao, G., Widmer, J., Stapleton, D., Teh, T., Cox, T. M., Kemp, B. E., & Witters, L. A. (1995) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/0167-4889(94)00222-z · Cited by 82 · see citing works
Consoli, A., Gomis, R., Halimi, S., Home, P., Mehnert, H., Strojek, K., & Gaal, L. V. (2004) · Diabetes & Metabolism · doi:10.1016/s1262-3636(07)70148-9 · Cited by 50 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Gallego, M., Eide, E. J., Woolf, M. F., Virshup, D. M., and Forger, D. B. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 10618 -10623
- Yoo, S. H., Ko, C. H., Lowrey, P. L., Buhr, E. D., Song, E. J., Chang, S., Yoo, O. J., Yamazaki, S., Lee, C., and Takahashi, J. S. (2005) Proc. Natl. Acad. Sci.
- Izumo, M., Johnson, C. H., and Yamazaki, S. (2003) Proc. Natl. Acad. Sci.
Cited by
Sorted by citations
The AMPK signalling pathway coordinates cell growth, autophagy and metabolism
Mihaylova, M. M., & Shaw, R. J. (2011) · Nature Cell Biology · doi:10.1038/ncb2329 · Cited by 2,923 · see citing works
Cellular and molecular mechanisms of metformin: an overview
Viollet, B., Guigas, B., Garcia, N. S., Leclerc, J., Foretz, M., & Andreelli, F. (2012) · Clinical Science · doi:10.1042/cs20110386 · Cited by 1,720 · see citing works
Self-citationTiming to perfection: the biology of central and peripheral circadian clocks
Albrecht, U. (2012) · Neuron · doi:10.1016/j.neuron.2012.04.006 · Cited by 915 · see citing works
Green, C. B., Takahashi, J. S., & Bass, J. (2008) · Cell · doi:10.1016/j.cell.2008.08.022 · Cited by 902 · see citing works
Circadian clocks and insulin resistance
Stenvers, D. J., Scheer, F. A. J. L., Schrauwen, P., la Fleur, S. E., & Kalsbeek, A. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0122-1 · Cited by 733 · see citing works
Crosstalk between components of circadian and metabolic cycles in mammals
Asher, G., & Schibler, U. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.01.006 · Cited by 601 · see citing works
Crosstalk between metabolism and circadian clocks
Reinke, H., & Asher, G. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0096-9 · Cited by 598 · see citing works
How might circadian rhythms control mood? Let me count the ways
McClung, C. A. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.02.019 · Cited by 507 · see citing works
Metabolism and Circadian Rhythms—Implications for Obesity
Froy, O. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0014 · Cited by 505 · see citing works
Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus
Tahrani, A. A., Barnett, A. H., & Bailey, C. J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.86 · Cited by 398 · see citing works
Circadian rhythms and exercise — re-setting the clock in metabolic disease
Gabriel, B. M., & Zierath, J. R. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0150-x · Cited by 382 · see citing works
Timed high-fat diet resets circadian metabolism and prevents obesity
Sherman, H., Genzer, Y., Cohen, R., Chapnik, N., Madar, Z., & Froy, O. (2012) · The FASEB Journal · doi:10.1096/fj.12-208868 · Cited by 360 · see citing works
Circadian control of glucose metabolism
Kalsbeek, A., la Fleur, S., & Fliers, E. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.03.002 · Cited by 338 · see citing works
Elgendy, M., Cirò, M., Hosseini, A., Weiszmann, J., Mazzarella, L., Ferrari, E., Cazzoli, R., Curigliano, G., DeCensi, A., Bonanni, B., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.03.007 · Cited by 299 · see citing works
The Cardiomyocyte Circadian Clock: Emerging Roles in Health and Disease
Durgan, D. J., & Young, M. E. (2010) · Circulation Research · doi:10.1161/circresaha.109.209957 · Cited by 277 · see citing works
Clocks, metabolism, and the epigenome
Feng, D., & Lazar, M. A. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.06.026 · Cited by 271 · see citing works
“Several studies place AMPK as a circadian clock regulator (Um et al., 2007, 2011; Vieira et al., 2008; Lamia et al., 2009) with two different mechanisms: AMPK activates CKIε and promotes PER2 degradation (Um et al., 2007), and AMPK phosphorylates CRY1 and destabilizes it (Lamia et al., 2009)…”
Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals
Kumar Jha, P., Challet, E., & Kalsbeek, A. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.01.024 · Cited by 235 · see citing works
Regulation of metabolism: the circadian clock dictates the time
Sahar, S., & Sassone-Corsi, P. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2011.10.005 · Cited by 222 · see citing works
Nutrients, Clock Genes, and Chrononutrition
Oike, H., Oishi, K., & Kobori, M. (2014) · Current Nutrition Reports · doi:10.1007/s13668-014-0082-6 · Cited by 198 · see citing works
Circadian Rhythms, Aging, and Life Span in Mammals
Froy, O. (2011) · Physiology · doi:10.1152/physiol.00012.2011 · Cited by 156 · see citing works
Barnea, M., Madar, Z., & Froy, O. (2009) · Endocrinology · doi:10.1210/en.2008-0944 · Cited by 138 · see citing works
Circadian Rhythms and Mitochondria: Connecting the Dots
Sardon Puig, L., Valera-Alberni, M., Cantó, C., & Pillon, N. J. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00452 · Cited by 113 · see citing works
Aging, circadian disruption and neurodegeneration: Interesting interplay
Verma, A. K., Singh, S., & Rizvi, S. I. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2022.112076 · Cited by 55 · see citing works
Mashaqi, S., & Gozal, D. (2020) · Sleep Medicine · doi:10.1016/j.sleep.2020.03.020 · Cited by 40 · see citing works
Central Circadian Clock Regulates Energy Metabolism
Ding, G., Gong, Y., Eckel-Mahan, K. L., & Sun, Z. (2018) · Advances in Experimental Medicine and Biology · doi:10.1007/978-981-13-1286-1_5 · Cited by 33 · see citing works
Metabolism as an integral cog in the mammalian circadian clockwork
Gamble, K. L., & Young, M. E. (2013) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.786672 · Cited by 18 · see citing works
- Authors
- Um, J. H., Yang, S., Yamazaki, S., Kang, H., Viollet, B., Foretz, M., & Chung, J. H.
- Affiliations
- National Institutes of Health (US)
- Vanderbilt University (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Chung, Jay H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 282
- Issue
- 29
- Pages
- 20794-20798
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2014422314
- Cited by
- 244
- References
- 25
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 10 · 2023: 17 · 2022: 11 · 2021: 14 · 2020: 14 · 2019: 13 · 2018: 10 · 2017: 15 · 2016: 16 · 2015: 11 · 2014: 19 · 2013: 19 · 2012: 15
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- 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
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- metformin, AMPK, casein kinase I epsilon, mPer2, circadian rhythm, circadian period, protein degradation, clock genes, type 2 diabetes, energy metabolism, AMP/ATP ratio, AMPKα2
- MeSH terms
- Amino Acid Sequence, Animals, Circadian Rhythm, Enzyme Activation, Gene Expression Regulation, Humans, Hypoglycemic Agents, Metformin, Molecular Sequence Data, Multienzyme Complexes, Nuclear Proteins, Transcription Factors, Protein Serine-Threonine Kinases, Mice, Knockout, Cell Cycle Proteins, Casein Kinase 1 epsilon, Mice, Rats, AMP-Activated Protein Kinases, Period Circadian Proteins
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 ›
Are you an author, or do you see a problem with this page? Request a review
