Altered Rhythm of Adrenal Clock Genes, StAR and Serum Corticosterone in VIP Receptor 2-Deficient Mice
Abstract
The circadian time-keeping system consists of clocks in the suprachiasmatic nucleus (SCN) and in peripheral organs including an adrenal clock linked to the rhythmic corticosteroid production by regulating steroidogenic acute regulatory protein (StAR). Clock cells contain an autonomous molecular oscillator based on a group of clock genes and their protein products. Mice lacking the VPAC2 receptor display disrupted circadian rhythm of physiology and behaviour, and therefore, we using real-time RT-PCR quantified (1) the mRNAs for the clock genes Per1 and Bmal1 in the adrenal gland and SCN, (2) the adrenal Star mRNA and (3) the serum corticosterone concentration both during a light/dark (L/D) cycle and at constant darkness in wild type (WT) and VPAC2 receptor-deficient mice (VPAC2-KO). We also examined if PER1 and StAR were co-localised in the adrenal steroidogenic cells. Per1 and Bmal1 mRNA showed a 24-h rhythmic expression in the adrenal of WT mice under L/D and dark conditions. During a L/D cycle, the adrenal clock gene rhythm in VPAC2-KO mice was phase-advanced by approximately 6 h compared to WT mice and became arrhythmic in constant darkness. A significant 24-h rhythmic variation in the adrenal Star mRNA expression and circulating corticosterone concentration was similarly phase-advanced during the L/D cycle. The loss of adrenal clock gene rhythm in the VPAC2 receptor knockout mice after transfer into constant darkness was accompanied by disappearance of rhythmicity in Star mRNA expression and serum corticosterone concentration. Double immunohistochemistry showed that the PER1 protein and StAR were co-localised in the same steroidogenic cells. Circulating corticosterone plays a role in the circadian timing system and the misaligned corticosterone rhythm in the VPAC2 receptor knockout mice could be involved in their abnormal rhythms of physiology.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Under a 12:12 light-dark cycle, VPAC2-KO mice adrenal clock gene rhythm and corticosterone rhythm was phase-advanced compared to wild-type mice, and when lighting was changed to constant darkness, the adrenal clock genes and corticosterone secretion became arrhythmic.
“Under a 12:12 LD cycle, the VPAC2-KO mice adrenal clock gene rhythm and corticosterone rhythm was phase-advanced compared to WT mice and when the lighting was changed to constant darkness, the adrenal clock genes and corticosterone secretion became arrhythmic173.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [173]
Cites
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
Dibner, C., Schibler, U., & Albrecht, U. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135821 · Cited by 2,421 · see citing works
A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells
Balsalobre, A., Damiola, F., & Schibler, U. (1998) · Cell · doi:10.1016/s0092-8674(00)81199-x · Cited by 2,001 · see citing works
Resetting of circadian time in peripheral tissues by glucocorticoid signaling
Balsalobre, A., Brown, S. A., Marcacci, L., Tronche, F., Kellendonk, C., Reichardt, H. M., Schütz, G., & Schibler, U. (2000) · Science · doi:10.1126/science.289.5488.2344 · Cited by 1,859 · see citing works
Methods for cosinor-rhythmometry.
Nelson, W. E., Tong, Y. L., Lee, J. K., & Franz Halberg, A. (1979) · PubMed · Cited by 1,701 · see citing works
Extensive and divergent circadian gene expression in liver and heart
Storch, K.-F., Lipan, O., Leykin, I., Viswanathan, N., Davis, F. C., Wong, W. H., & Weitz, C. J. (2002) · Nature · doi:10.1038/nature744 · Cited by 1,509 · see citing works
Temperature as a Universal Resetting Cue for Mammalian Circadian Oscillators
Buhr, E. D., Yoo, S.-H., & Takahashi, J. S. (2010) · Science · doi:10.1126/science.1195262 · Cited by 917 · see citing works
Feast and Famine: Critical Role of Glucocorticoids with Insulin in Daily Energy Flow
Dallman, M. F., Strack, A. M., Akana, S. F., Bradbury, M. J., Hanson, E. S., Scribner, K. A., & Smith, M. (1993) · Frontiers in Neuroendocrinology · doi:10.1006/frne.1993.1010 · Cited by 796 · cited 2× · see citing works
“NS not significant role of the rhythmic corticosterone secretion is to be proactive in regulation of energy balance for the activity phase (Dallman et al. 1993).”
Abrahamson, E. E., & Moore, R. Y. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02890-6 · Cited by 788 · see citing works
Aton, S. J., Colwell, C. S., Harmar, A. J., Waschek, J. A., & Herzog, E. D. (2005) · Nature Neuroscience · doi:10.1038/nn1419 · Cited by 764 · see citing works
Light activates the adrenal gland: Timing of gene expression and glucocorticoid release
Ishida, A., Mutoh, T., Ueyama, T., Bando, H., Masubuchi, S., Nakahara, D., Tsujimoto, G., & Okamura, H. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.09.009 · Cited by 589 · see citing works
The VPAC2 Receptor Is Essential for Circadian Function in the Mouse Suprachiasmatic Nuclei
Harmar, A. J., Marston, H. M., Shen, S., Spratt, C., West, K. M., Sheward, W. J., Morrison, C. F., Dorin, J. R., Piggins, H. D., Reubi, J.-C., et al. (2002) · Cell · doi:10.1016/s0092-8674(02)00736-5 · Cited by 549 · see citing works
Strange vision: ganglion cells as circadian photoreceptors
Berson, D. (2003) · Trends in Neurosciences · doi:10.1016/s0166-2236(03)00130-9 · Cited by 546 · see citing works
Characterization of Peripheral Circadian Clocks in Adipose Tissues
Zvonic, S., Ptitsyn, A. A., Conrad, S. A., Scott, L. K., Floyd, Z. E., Kilroy, G. E., Wu, X., Goh, B. C. K., Mynatt, R. L., & Gimble, J. M. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-0873 · Cited by 495 · see citing works
Glucocorticoids and the circadian clock
Dickmeis, T. (2009) · Journal of Endocrinology · doi:10.1677/joe-08-0415 · Cited by 494 · see citing works
Interactions of the circadian CLOCK system and the HPA-axis
Nader, N., Chrousos, G. P., & Kino, T. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.12.011 · Cited by 449 · see citing works
Maywood, E. S., Reddy, A. B., Wong, G. K. Y., O'Neill, J. S., O'Brien, J. A., McMahon, D. G., Harmar, A. J., Okamura, H., & Hastings, M. H. (2006) · Current Biology · doi:10.1016/j.cub.2006.02.023 · Cited by 438 · see citing works
Usdin, T. B. (1994) · Endocrinology · doi:10.1210/en.135.6.2662 · Cited by 433 · see citing works
Do Corticosteroids Damage the Brain?
Herbert, J., Goodyer, I. M., Grossman, A. B., Hastings, M. H., de Kloet, E. R., Lightman, S. L., LUPIEN, S. J., Roozendaal, B., & Seckl, J. R. (2006) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2006.01429.x · Cited by 384 · see citing works
Disrupted circadian rhythms in VIP- and PHI-deficient mice
Colwell, C. S., Michel, S. H., Itri, J. N., Rodriguez, W. I., Nguyen‐Van‐Tam, J. S., Lelièvre, V., Hu, Z., Liu, X., & Waschek, J. A. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00200.2003 · Cited by 384 · see citing works
Son, G. H., Chung, S., Choe, H. K., Kim, H.-D., Baik, S. M., Lee, H., Lee, H., Choi, S., Sun, W., Kim, H., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806962106 · Cited by 316 · see citing works
Glucocorticoid action networks and complex psychiatric and/or somatic disorders
Chrousos, G. P., & Kino, T. (2007) · Stress · doi:10.1080/10253890701292119 · Cited by 292 · cited 1× · see citing works
“Glucocorticoids are heavily involved in human pathophysiology (Chrousos and Kino 2007), and it is likely that the observed abnormality in the adrenocortical function in the VPAC2-KO mice can make it a useful model.”
Glucocorticoids: exemplars of multi-tasking
Buckingham, J. C. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706456 · Cited by 276 · see citing works
Lamont, E. W., Robinson, B., Stewart, J., & Amir, S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500901102 · Cited by 256 · see citing works
Usdin, T. B., Bonner, T. I., & Mezey, É. (1994) · Endocrinology · doi:10.1210/endo.135.6.7988457 · Cited by 251 · see citing works
Oster, H., Damerow, S., Hut, R. A., & Gregor Eichele, C. (2006) · Journal of Biological Rhythms · doi:10.1177/0748730406293053 · Cited by 231 · see citing works
Rhodes, M. E., & Rubín, R. T. (1999) · Brain Research Reviews · doi:10.1016/s0165-0173(99)00011-9 · Cited by 215 · see citing works
Vasoactive intestinal peptide and the mammalian circadian system
Vosko, A. M., Schroeder, A., Loh, D. H., & Colwell, C. S. (2007) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2007.04.018 · Cited by 183 · see citing works
Fuhrmann, T. R., Timberg, R., King, S. R., Hales, K. H., Hales, D. B., Stocco, D. M., & Orly, J. (1998) · Endocrinology · doi:10.1210/endo.139.1.5694 · Cited by 181 · see citing works
Amir, S., Lamont, E. W., Robinson, B., & Stewart, J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4488-03.2004 · Cited by 175 · see citing works
Diurnal Rhythmicity of the Clock Genes Per1 and Per2 in the Rat Ovary
Fahrenkrug, J., Georg, B., Hannibal, J., Hindersson, P., & Gräs, S. (2006) · Endocrinology · doi:10.1210/en.2006-0305 · Cited by 156 · see citing works
Self-citationLocalization of the Steroidogenic Acute Regulatory Protein in Human Tissues1
Pollack, S. E., Furth, E. E., Kallen, C. B., Arakane, F., Kiriakidou, M., Kozarsky, K., & Strauss, J. F. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.12.4445 · Cited by 140 · see citing works
The adrenal peripheral clock: Glucocorticoid and the circadian timing system
Son, G. H., Chung, S., & Kim, K. (2011) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2011.07.003 · Cited by 136 · cited 2× · see citing works
“Recent progress has now defined the pivotal role of the adrenal-intrinsic oscillator in the rhythmicity of corticosterone synthesis and secretion (Son et al. 2011).”
The distribution of vasoactive intestinal peptide in the rat adrenal cortex and medulla
Holzwarth, M. A. (1984) · Journal of the Autonomic Nervous System · doi:10.1016/0165-1838(84)90041-9 · Cited by 121 · see citing works
Localization of the Steroidogenic Acute Regulatory Protein in Human Tissues
Pollack, S. E. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.12.4243 · Cited by 111 · see citing works
Immunohistochemical evidence for a local VIP‐ergic neuron system in the adrenal gland of the rat
Hökfelt, T. G. M., Lundberg, J. M., Schultzberg, M., & Fahrenkrug, J. (1981) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1981.tb06944.x · Cited by 109 · see citing works
Self-citationPeriod gene expression in mouse endocrine tissues
Bittman, E. L., Doherty, L. F., Huang, L., & Paroskie, A. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00783.2002 · Cited by 107 · see citing works
Asnicar, M., Koster, A. M., Heiman, M. L., Tinsley, F. C., Smith, D. P., Galbreath, E. J., Fox, N. W., Ma, Y. L., Blum, W. F., & Hsiung, H. M. (2002) · Endocrinology · doi:10.1210/en.2002-220354 · Cited by 103 · see citing works
Hughes, A. T. L., Fahey, B., Cutler, D. J., Coogan, A. N., & Piggins, H. D. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.5345-03.2004 · Cited by 99 · see citing works
Daily Variation in Concentration of Plasma Corticosteroid in Hypophysectomized Rats
MEIER, A. H. (1976) · Endocrinology · doi:10.1210/endo-98-6-1475 · Cited by 95 · see citing works
Entrainment to Feeding but Not to Light: Circadian Phenotype of VPAC2Receptor-Null Mice
Sheward, W. J., Maywood, E. S., French, K. L., Horn, J. M., Hastings, M. H., Seckl, J. R., Holmes, M. C., & Harmar, A. J. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4843-06.2007 · Cited by 86 · see citing works
Melanopsin containing retinal ganglion cells are light responsive from birth
Hannibal, J., & Fahrenkrug, J. (2004) · Neuroreport · doi:10.1097/00001756-200410250-00003 · Cited by 83 · see citing works
Self-citationFahrenkrug, J., & Hannibal, J. (1998) · Neuroscience · doi:10.1016/s0306-4522(97)00474-0 · Cited by 80 · see citing works
Self-citationNielsen, H. S., Hannibal, J., Knudsen, S. M., & Fahrenkrug, J. (2001) · Neuroscience · doi:10.1016/s0306-4522(00)00563-7 · Cited by 79 · see citing works
Self-citationFahrenkrug, J., Hannibal, J., & Georg, B. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01651.x · Cited by 77 · see citing works
Self-citationMetabolic rhythm abnormalities in mice lacking VIP-VPAC2signaling
Bechtold, D. A., Brown, T. M., Luckman, S. M., & Piggins, H. D. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00667.2007 · Cited by 75 · see citing works
Κalamatianos, T., Kalló, I., Piggins, H. D., & Coen, C. W. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.20168 · Cited by 70 · see citing works
Vasoactive Intestinal Peptide Is Critical for Circadian Regulation of Glucocorticoids
Loh, D. H., Abad, C., Colwell, C. S., & Waschek, J. A. (2008) · Neuroendocrinology · doi:10.1159/000140676 · Cited by 69 · see citing works
Torres‐Farfan, C., Serón‐Ferré, M., Dinet, V., & Korf, H. (2005) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2005.00279.x · Cited by 68 · see citing works
Melanopsin: a novel photopigment involved in the photoentrainment of the brain's biological clock?
Hannibal, J., & Fahrenkrug, J. (2002) · Annals of Medicine · doi:10.1080/078538902320772151 · Cited by 66 · see citing works
Self-citationLive imaging of altered period1 expression in the suprachiasmatic nuclei of Vipr2−/− mice1
Hughes, A. T. L., Guilding, C., Lennox, L., Samuels, R. E., McMahon, D. G., & Piggins, H. D. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05520.x · Cited by 59 · see citing works
Loh, D. H., Dragich, J. M., Kudo, T., Schroeder, A., Nakamura, T. J., Waschek, J. A., Block, G. D., & Colwell, C. S. (2011) · Journal of Biological Rhythms · doi:10.1177/0748730411401740 · Cited by 51 · see citing works
Hannibal, J., Hsiung, H. M., & Fahrenkrug, J. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00599.2010 · Cited by 49 · see citing works
Self-citationDe novo synthesis of corticosteroids in hamster adrenal glands
Lehoux, J., & Lefèbvre, A. (1980) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(80)90310-6 · Cited by 48 · see citing works
Circadian regulation of cardiovascular function: a role for vasoactive intestinal peptide
Schroeder, A., Loh, D. H., Jordan, M. C., Roos, K. P., & Colwell, C. S. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00190.2010 · Cited by 39 · see citing works
Fahrenkrug, J., Hannibal, J., Honoré, B., et al. (2005) · Journal of Molecular Neuroscience · doi:10.1385/jmn:25:3:251 · Cited by 26 · see citing works
Self-citationChamber-dependent circadian expression of cardiac natriuretic peptides
Goetze, J. P., Georg, B., Jørgensen, H. L., & Fahrenkrug, J. (2009) · Regulatory Peptides · doi:10.1016/j.regpep.2009.12.010 · Cited by 21 · see citing works
Self-citationCorticosterone and Activity: The Long Arms of the Clock Talk Back
Buijs, R. M., & Escobar, C. (2007) · Endocrinology · doi:10.1210/en.2007-0926 · Cited by 20 · see citing works
Thompson, W. E., Powell, J. M., Thomas, K. H., & Whittaker, J. A. (1999) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215549904700606 · Cited by 19 · see citing works
Georg, B., Hannibal, J., & Fahrenkrug, J. (2006) · Brain Research · doi:10.1016/j.brainres.2006.12.001 · Cited by 16 · see citing works
Self-citationPhase response profile of hamster adrenal organ cultures treated with acth and exogenous steroid
Andrews, R. V. (1980) · Comparative Biochemistry and Physiology Part A Physiology · doi:10.1016/0300-9629(80)90276-5 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Circadian rhythm disruption and mental health
Walker, W. H., Walton, J. C., DeVries, A. C., & Nelson, R. J. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0694-0 · Cited by 1,030 · see citing works
In synch but not in step: Circadian clock circuits regulating plasticity in daily rhythms
Evans, J. A., & Gorman, M. R. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.01.072 · Cited by 49 · see citing works
- Authors
- Fahrenkrug, J., Georg, B., Hannibal, J., & Jørgensen, H. L.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Fahrenkrug, Jan
- Venue
- Journal of Molecular Neuroscience
- Published
- 2012-05-24
- Volume
- 48
- Issue
- 3
- Pages
- 584-596
- ISSN
- 0895-8696 (ISSN-L)
- 1559-1166
- OpenAlex
- W2038668908
- Cited by
- 27
- References
- 61
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 2 · 2016: 3 · 2014: 3 · 2013: 2
- FWCI
- 1.74
- Type
- book chapter
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- VPAC2 receptor, circadian rhythm, corticosterone, steroidogenic acute regulatory protein, Per1, Bmal1, suprachiasmatic nucleus, steroidogenesis, constant darkness, phase advance
- MeSH terms
- Steroidogenic Acute Regulatory Protein, Adrenal Cortex, Adrenal Medulla, Animals, Circadian Rhythm, Corticosterone, Darkness, Gene Expression Regulation, Light, Male, Mice, Inbred C57BL, Phosphoproteins, RNA, Messenger, Suprachiasmatic Nucleus, In Situ Hybridization, Mice, Knockout, Receptors, Vasoactive Intestinal Peptide, Type II, Mice, ARNTL Transcription Factors, Period Circadian Proteins, Real-Time Polymerase Chain Reaction
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
