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Glucocorticoid regulation of the circadian clock modulates glucose homeostasis
Open accessAbstract
Circadian clock genes are regulated by glucocorticoids; however, whether this regulation is a direct or secondary effect and the physiological consequences of this regulation were unknown. Here, we identified glucocorticoid response elements (GREs) at multiple clock genes and showed that 3 were directly regulated by the glucocorticoid receptor. We determined that a GRE within the core clock gene Per2 was continuously occupied during rhythmic expression and essential for glucocorticoid regulation of that gene in vivo. We further demonstrated that mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. We conclude that Per2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.
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“Resetting of the peripheral clock occurs through well-defined molecular mechanisms that involve direct interaction of glucocorticoids, glucocorticoid response elements and the regulatory regions of core clock genes Bmal1, Cry1, Per1 and Per2 [63, 64].”
From Sleep, testosterone and cortisol balance, and ageing men (2022) · cites this paper as [64]
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“Per2 null mice exhibit no glucocorticoid oscillations, indicating that PER2 may also impact glucocorticoid receptor (GR)-dependent glucose metabolism [24,25].”
From Circadian control of glucose metabolism (2014) · cites this paper as [24]
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THE CROSSTALK BETWEEN PHYSIOLOGY AND CIRCADIAN CLOCK PROTEINS
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“Functional glucocorticoid response elements (GREs) in the promoter regions of Per1, Per2, and E4bp4 have also been reported as possible factors in the signaling mechanisms of molecular clocks [26, 27], and the expression of Rev-erba in the liver has been reported to decrease in response to glucocorticoid treatment via…”
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“The Nfil3 gene locus contains a GRE motif (6), and its expression is reduced in GR-deficient T cells in the early phase of Th2 differentiation.”
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“Consistent with the results of the ChIP assay, GBS-mediated luciferase activities were increased by DEX treatment in WT and Bmal1 / MEFs (Supplementary Figure S4).”
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“Such external and internal misalignment is associated with several health disorders, and GC rhythms play an important role in this context due to their capacity to reset tissue clocks via GR signaling (Balsalobre et al., 2000; So et al., 2009; Lamia et al., 2011) (Figure 2B).”
BackgroundCistromic Reprogramming of the Diurnal Glucocorticoid Hormone Response by High-Fat Diet
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“Several studies have shown both genetic and physical interactions between GR and the core clock machinery; functional GREs have been identified in the Per1 and Per2 regulatory regions, while the Rev-erbα promoter was found to be repressed by GR (So et al., 2009; Torra et al., 2000; Yamamoto et al., 2005).”
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“The timing/entrainment of these rhythms may be related to the presence of a glucocorticoid response element (GRE) and cAMP response element in the promoter region of both genes (Colwell, 2011; So et al., 2009; T. Yamamoto et al., 2005).”
BackgroundHPA Axis Interactions with Behavioral Systems
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Glucocorticoid receptor modulators
Meijer, O. C., Koorneef, L. L., & Kroon, J. (2018) · Annales d Endocrinologie · doi:10.1016/j.ando.2018.03.004 · Cited by 93
Circadian Synchrony: Sleep, Nutrition, and Physical Activity
Healy, K. L., Morris, A. R., & Liu, A. C. (2021) · Frontiers in Network Physiology · doi:10.3389/fnetp.2021.732243 · Cited by 98
“BMAL1/CLOCK activity is negatively regulated by transcriptional repressors PERIOD (PER1/2/3) and CRYPTOCHROME (CRY1/2) (Sato et al., 2006; Takahashi, 2017).”
InfluentialCircadian control of pain and neuroinflammation
Segal, J. P., Tresidder, K. A., Bhatt, C., Gilron, I., & Ghasemlou, N. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24150 · Cited by 97
Circadian Clocks and Inflammation: Reciprocal Regulation and Shared Mediators
Cermakian, N., Westfall, S., & Kießling, S. (2014) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-014-0286-x · Cited by 95
“LPS administration suppresses the expression of Per1 and Per2 in the liver (Okada et al. 2008).”
BackgroundInfluentialMultilevel Interactions of Stress and Circadian System: Implications for Traumatic Stress
Agorastos, A., Nicolaides, N. C., Bozikas, V. P., Chrousos, G. P., & Pervanidou, P. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.01003 · Cited by 89
Circadian regulation of mitochondrial uncoupling and lifespan
Ulgherait, M., Chen, A., McAllister, S. F., Kim, H. X., Delventhal, R., Wayne, C. R., Garcia, C., Recinos, Y., Oliva, M. K., Canman, J. C., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15617-x · Cited by 91
Clinical reviews in allergy and immunology
Leung, D. Y. M., Ledford, D. K., Wechsler, M. E., Fulkerson, P. C., Bochner, B. S., Gauvreau, G. M., Gleich, G. J., Henkel, T., Kolbeck, R., Mathur, S. K., et al. (2012) · Cited by 87
Liquid Crystal Monomer: A Potential PPARγ Antagonist
Zhao, H., Li, C., Naik, M. Y., Wu, J., Cardilla, A., Liu, M., Zhao, F., Snyder, S. A., Xia, Y. F., Su, G., et al. (2023) · Environmental Science & Technology · doi:10.1021/acs.est.2c08109 · Cited by 87
Circadian Rhythm Gene Period 3 Is an Inhibitor of the Adipocyte Cell Fate
Costa, M. J. D. C., So, A. Y., Kaasik, K., Krueger, K. C., Pillsbury, M. L., Fu, Y., Ptáček, L. J., Yamamoto, K. R., & Feldman, B. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.164558 · Cited by 83
Self-citationThe circadian clock, metabolism and obesity
Albrecht, U. (2017) · Obesity Reviews · doi:10.1111/obr.12502 · Cited by 84
“This suggests that GR is a critical regulator of clock gene expression (52).”
BackgroundSleep, testosterone and cortisol balance, and ageing men
Liu, P. Y., & Reddy, R. T. (2022) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-022-09755-4 · Cited by 80
“Resetting of the peripheral clock occurs through well-defined molecular mechanisms that involve direct interaction of glucocorticoids, glucocorticoid response elements and the regulatory regions of core clock genes Bmal1, Cry1, Per1 and Per2 [63, 64].”
BackgroundRole of the Circadian Clock in the Metabolic Syndrome and Nonalcoholic Fatty Liver Disease
Shetty, A., Hsu, J. W., Manka, P. P., & Syn, W. (2018) · Digestive Diseases and Sciences · doi:10.1007/s10620-018-5242-x · Cited by 85
Nakamura, Y., Harama, D., Shimokawa, N., Hara, M., Suzuki, R., Tahara, Y., Ishimaru, K., Katoh, R., Okumura, K., Ogawa, H., et al. (2011) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2011.02.006 · Cited by 79
Hoyt, K. R., & Obrietan, K. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00537-9 · Cited by 77
“The process by which rhythmic release of GC drives clock gene rhythms appears to be mediated, at least in part, via a transcriptional mechanism in which GC drives glucocorticoid responsive element- (GRE) mediated expression of core clock genes [55].”
BackgroundEndocrine regulation of circadian rhythms
Begemann, K., Rawashdeh, O., Olejniczak, I., Pilorz, V., de Assis, L. V. M., Osorio-Mendoza, J., & Oster, H. (2025) · npj Biological Timing and Sleep · doi:10.1038/s44323-025-00024-6 · Cited by 93
“However, several clock genes also contain glucocorticoid response elements 23 .”
Entrainment of peripheral clock genes by cortisol
Mavroudis, P. D., Scheff, J. D., Calvano, S. E., Lowry, S. F., & Androulakis, I. P. (2012) · Physiological Genomics · doi:10.1152/physiolgenomics.00001.2012 · Cited by 77
Human studies on hypothalamo-pituitary-adrenal (HPA) axis
Liyanarachchi, K., Ross, R. J. M., & Debono, M. (2017) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2017.10.011 · Cited by 83
Nutrition, metabolism, and epigenetics: pathways of circadian reprogramming
Sato, T., & Sassone‐Corsi, P. (2022) · EMBO Reports · doi:10.15252/embr.202152412 · Cited by 77
“The promoter region of Per contains a GR-binding region, and Per gene expression rapidly increases after GR activation (Yamamoto et al , 2005; So et al , 2009).”
Circadian Variation in Placental and Hepatic Clock Genes in Rat Pregnancy
Wharfe, M. D., Mark, P. J., & Waddell, B. J. (2011) · Endocrinology · doi:10.1210/en.2011-0081 · Cited by 74
“Previous studies in vitro show that dexamethasone up-regulates Per2 expression in mesenchymal stem cells (25) and all three Per genes and Cry1 in fibroblasts (26).”
BackgroundGabarre, P., Loens, C., Tamzali, Y., Barrou, B., Jaisser, F., & Tourret, J. (2021) · American Journal of Transplantation · doi:10.1111/ajt.16836 · Cited by 76
Per2 Mutation Recapitulates the Vascular Phenotype of Diabetes in the Retina and Bone Marrow
Bhatwadekar, A. D., Yan, Y., Qi, X., Thinschmidt, J. S., Neu, M. B., Calzi, S. L., Shaw, L. C., Dominiguez, J. M., Busik, J. V., Lee, C., et al. (2012) · Diabetes · doi:10.2337/db12-0172 · Cited by 73
“Per2 is an important component of the glucocorticoid regulatory pathway, and disruption of glucocorticoid regulation and leptin regulation may be partly responsible for the enhanced glucose sensitivity observed in the Per2 mutant mice (26).”
BackgroundGetting rhythm: how do babies do it?
Joseph, D., Chong, N. W., Shanks, M. E., Rosato, E., Taub, N. A., Petersen, S. A., Symonds, M. E., Whitehouse, W. P., & Wailoo, M. P. (2014) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/archdischild-2014-306104 · Cited by 71
Functional Organization of Neuronal and Humoral Signals Regulating Feeding Behavior
Schwartz, G. J., & Zeltser, L. M. (2013) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161125 · Cited by 67
“The Per2 gene has GC-responsive elements in its promoter; eliminating them abolishes CORT’s effects on glucose homeostasis and leptin levels (115).”
Cedernaes, J., Lampola, L., Axelsson, E. K., Liethof, L., Hassanzadeh, S., Yeganeh, A., Broman, J., Schiöth, H. B., & Benedict, C. (2015) · Journal of Sleep Research · doi:10.1111/jsr.12340 · Cited by 69
Komoto, S., Kondo, H., Fukuta, O., & Togari, A. (2012) · Chronobiology International · doi:10.3109/07420528.2011.636496 · Cited by 65
“Other groups also reported that glucocorticoid synchronizes circadian rhythms in gene expression in some cell types (Balsalobre et al., 1998; Burioka et al., 2005; Fujioka et al., 2006; Reddy et al., 2007; So et al., 2009).”
BackgroundCircadian Clocks Make Metabolism Run
Sinturel, F., Petrenko, V., & Dibner, C. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.01.018 · Cited by 66
Chronic mild stress alters circadian expressions of molecular clock genes in the liver
Takahashi, K., Yamada, T., Tsukita, S., Kaneko, K., Shirai, Y., Munakata, Y., Ishigaki, Y., Imai, J., Uno, K., Hasegawa, Y., et al. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00388.2012 · Cited by 63
“In vitro studies have demonstrated that 347 glucocorticoids stimulate the transcriptional rhythmicities of Per1 (5), NPAS2 (45), 348 Cry1 (5), Bmal1 and Clock (36), all of which were found to show altered oscillations in 349 the present study.”
BackgroundInfluentialPantazopoulos, H., Wiseman, J. T., Markota, M., Ehrenfeld, L., & Berretta, S. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.04.006 · Cited by 71
“also directly regulate CLOCK genes through glucocorticoid response elements located in the promoter region of Per1 and Per2 genes (142, 143).”
Lechasseur, A., Jubinville, É., Routhier, J., Bérubé, J., Hamel-Auger, M., Talbot, M., Lamothe, J., Aubin, S., Paré, M., Beaulieu, M., et al. (2017) · Physiological Reports · doi:10.14814/phy2.13440 · Cited by 63
“Glucose metabolism (Panda et al. 2002; So et al. 2009; Bass and Takahashi 2010), immune and inflammatory responses (Oishi et al.”
Background
Metadata
- Authors
- So, A. Y.-L., Bernal, T. U., Pillsbury, M. L., Yamamoto, K. R., & Feldman, B. J.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-10-13
- Volume
- 106
- Issue
- 41
- Pages
- 17582-17587
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2757402
- OpenAlex
- W1998522501
- Cited by
- 431
- References
- 51
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 37 · 2023: 19 · 2022: 36 · 2021: 28 · 2020: 32 · 2019: 28 · 2018: 22 · 2017: 28 · 2016: 33 · 2015: 23 · 2014: 25 · 2013: 20 · 2012: 18
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, San Francisco
- National Cancer Institute (CA20535, R01CA020535, R37CA020535)
- National Institute of General Medical Sciences (R25GM056847, GM 56847)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK073697, DK73697)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- glucocorticoids, circadian clock, clock genes, glucocorticoid response element, glucocorticoid receptor, Per2, glucose homeostasis, insulin resistance, impaired glucose tolerance, leptin, muscle atrophy, peripheral clocks
- MeSH terms
- Animals, Circadian Rhythm, Gene Expression Regulation, Glucocorticoids, Glucose, Homeostasis, Nuclear Proteins, Transcription Factors, Transcription, Genetic, Polymerase Chain Reaction, Cell Cycle Proteins, Leptin, Mice, Period Circadian Proteins, Mesenchymal Stem Cells
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