Adrenergic regulation of clock gene expression in mouse liver.
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Journal: 2003/July - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether injection of adrenaline/noradrenaline (epinephrine/norepinephrine) or sympathetic nerve stimulation could induce mPer gene expression in mouse liver. Acute administration of adrenaline or noradrenaline increased mPer1 but not mPer2 expression in the liver of mice in vivo and in hepatic slices in vitro. Electrical stimulation of the sympathetic nerves or adrenaline injection caused an elevation of bioluminescence in the liver area of transgenic mice carrying mPer1 promoter-luciferase. Under a light-dark cycle, destruction of the SCN flattened the daily rhythms of not only mPer1, mPer2, and mBmal1 genes but also noradrenaline content in the liver. Daily injection of adrenaline, administered at a fixed time for 6 days, recovered oscillations of mPer2 and mBmal1 gene expression in the liver of mice with SCN lesion on day 7. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, on the basis of the present results, activation of the sympathetic nerves through noradrenaline and/or adrenaline release was a factor controlling the peripheral clock.
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Proc Natl Acad Sci U S A 100(11): 6795-6800
PMID: 12754374

Adrenergic regulation of clock gene expression in mouse liver

Department of Pharmacology and Brain Science, School of Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan
Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-Ku, Fukuoka 812-8582, Japan
Division of Molecular Brain Science, Department of Brain Sciences, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Department of Electronic Engineering, Tohoku Institute of Technology, Sendai 982-8577, Japan
To whom correspondence should be addressed. E-mail: pj.adesaw@satabihs.
Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD
Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD
Received 2002 Nov 7; Accepted 2003 Mar 3.
Copyright © 2003, The National Academy of Sciences

Abstract

A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether injection of adrenaline/noradrenaline (epinephrine/norepinephrine) or sympathetic nerve stimulation could induce mPer gene expression in mouse liver. Acute administration of adrenaline or noradrenaline increased mPer1 but not mPer2 expression in the liver of mice in vivo and in hepatic slices in vitro. Electrical stimulation of the sympathetic nerves or adrenaline injection caused an elevation of bioluminescence in the liver area of transgenic mice carrying mPer1 promoter-luciferase. Under a light–dark cycle, destruction of the SCN flattened the daily rhythms of not only mPer1, mPer2, and mBmal1 genes but also noradrenaline content in the liver. Daily injection of adrenaline, administered at a fixed time for 6 days, recovered oscillations of mPer2 and mBmal1 gene expression in the liver of mice with SCN lesion on day 7. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, on the basis of the present results, activation of the sympathetic nerves through noradrenaline and/or adrenaline release was a factor controlling the peripheral clock.

Abstract

The suprachiasmatic nucleus (SCN) houses a master pacemaker that regulates behavioral and physiological circadian rhythms such as locomotor activity, body temperature, and endocrine release (1). Recently, it has been established that a number of putative clock genes such as Per1, Per2, Per3, Clock, Bmal1, Cry1, and Cry2 are expressed in the SCN, and the molecular dissection of circadian clock systems has produced a functional model of the transcription/translation feedback loops used by theses clock genes (2). This functional model can be applied to not only the SCN (3) but also the peripheral organs (4, 5) as well as rat-1 cells (6).

Destruction of the SCN abolishes not only the circadian rhythms of adrenocorticotropic hormone, glucocorticoid (7, 8), and locomotor activity (9), but also the rhythms in Per gene expression in the peripheral tissues (5, 9, 10). Thus, the SCN may communicate timing information to a variety of peripheral tissues via neural (11) and humoral (12) connections to help regulate such fundamental physiological functions such as energy metabolism, food and fluid balance, and cardiovascular, immune, and reproductive responses.

Over the past few years, use of the pseudorabies virus, a transsynaptic tract tracer, has allowed us to map neural connections between the SCN and peripheral tissues in several physiological systems (13). Communication between the SCN and peripheral tissues occurs through autonomic nervous systems involving the sympathetic and parasympathetic neurons. Sympathetic nervous system innervation of the pineal gland and sympathetic outflow from the brain to white adipose tissue demonstrated SCN–peripheral tissue connections (14, 15). Knowledge of integration of the central and peripheral clocks has led to perspective that involves a multioscillatory system in mammals (16).

Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats (17), whether these pathways convey timing information from the SCN to the liver has yet to be established. Therefore, we examined whether adrenergic stimulation could reset the peripheral clock in mouse liver.

Acknowledgments

This study was partially supported by grants from the Japanese Ministry of Education, Science, Sports, and Culture (11233207, 13470016, and 12877385 to S.S.), the Kanae Foundation for Life and Socio- and Medical Science and the Inamori Foundation (to S.Y.), and the Cosmetology Research Foundation (to H.O.), and by Special Coordination Funds from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (to S.S. and H.O.).

Acknowledgments

Notes

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: SCN, suprachiasmatic nucleus; ZT, Zeitgeber time (in hours); RLU, relative light units; 6-OHDA, 6-hydroxydopamine; MAPK, mitogen-associated protein kinase; PKA, protein kinase A.

Notes
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: SCN, suprachiasmatic nucleus; ZT, Zeitgeber time (in hours); RLU, relative light units; 6-OHDA, 6-hydroxydopamine; MAPK, mitogen-associated protein kinase; PKA, protein kinase A.

Footnotes

Mendoza, J. Y., Avila, J., Aguilar-Roblero, R. A. & Escobar, C., 31st Annual Meeting of the Society for Neuroscience, Nov. 10–15, 2001, San Diego, p. 183.116 (abstr.).

Footnotes

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