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Altered Rhythm of Adrenal Clock Genes, StAR and Serum Corticosterone in VIP Receptor 2-Deficient Mice

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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.

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Abbreviations

L/D:

12:12 h light/dark cycle

WT:

Wild type

Per1 :

Period1

Bmal1 :

Brain and muscle ARNT-like protein 1

RT-PCR:

Reverse trascriptase polymerase chain reaction

VIP:

Vasoactive intestinal polypeptide

VPAC2:

Vasoactive intestinal polypeptide receptor 2

KO:

Knockout

SCN:

Suprachiasmatic nucleus

StAR:

Steroidogenic acute regulatory protein

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Acknowledgments

The skilful technical assistance of Anita Hansen, Yvonne Søndergaard and Tina Wintersø is gratefully acknowledged. The study was supported by the Danish Biotechnology Center for Cellular Communication.

Conflict of interest

The authors have nothing to disclose.

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Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Health Sciences, Bispebjerg Hospital, University of Copenhagen, Copenhagen, 2400, Denmark

    Jan Fahrenkrug, Birgitte Georg, Jens Hannibal & Henrik Løvendahl Jørgensen

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  1. Jan Fahrenkrug
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  2. Birgitte Georg
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  3. Jens Hannibal
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  4. Henrik Løvendahl Jørgensen
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Correspondence to Jan Fahrenkrug.

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Fahrenkrug, J., Georg, B., Hannibal, J. et al. Altered Rhythm of Adrenal Clock Genes, StAR and Serum Corticosterone in VIP Receptor 2-Deficient Mice. J Mol Neurosci 48, 584–596 (2012). https://doi.org/10.1007/s12031-012-9804-7

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  • DOI: https://doi.org/10.1007/s12031-012-9804-7

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