Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling
Article first published online: 28 OCT 2011
© 2011 John Wiley & Sons A/S
Journal of Pineal Research
Volume 52, Issue 2, pages 139–166, March 2012
How to Cite
Hardeland, R., Madrid, J. A., Tan, D.-X. and Reiter, R. J. (2012), Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. Journal of Pineal Research, 52: 139–166. doi: 10.1111/j.1600-079X.2011.00934.x
- Issue published online: 6 FEB 2012
- Article first published online: 28 OCT 2011
- Accepted manuscript online: 27 SEP 2011 09:46AM EST
- Received September 1, 2011; Accepted September 23, 2011.
- age-related diseases;
- melatonin receptors;
- mood disorders;
- peripheral oscillators
Abstract: Evidence is accumulating regarding the importance of circadian core oscillators, several associated factors, and melatonin signaling in the maintenance of health. Dysfunction of endogenous clocks, melatonin receptor polymorphisms, age- and disease-associated declines of melatonin likely contribute to numerous diseases including cancer, metabolic syndrome, diabetes type 2, hypertension, and several mood and cognitive disorders. Consequences of gene silencing, overexpression, gene polymorphisms, and deviant expression levels in diseases are summarized. The circadian system is a complex network of central and peripheral oscillators, some of them being relatively independent of the pacemaker, the suprachiasmatic nucleus. Actions of melatonin on peripheral oscillators are poorly understood. Various lines of evidence indicate that these clocks are also influenced or phase-reset by melatonin. This includes phase differences of core oscillator gene expression under impaired melatonin signaling, effects of melatonin and melatonin receptor knockouts on oscillator mRNAs or proteins. Cross-connections between melatonin signaling pathways and oscillator proteins, including associated factors, are discussed in this review. The high complexity of the multioscillator system comprises alternate or parallel oscillators based on orthologs and paralogs of the core components and a high number of associated factors with varying tissue-specific importance, which offers numerous possibilities for interactions with melatonin. It is an aim of this review to stimulate research on melatonin signaling in peripheral tissues. This should not be restricted to primary signal molecules but rather include various secondarily connected pathways and discriminate between direct effects of the pineal indoleamine at the target organ and others mediated by modulation of oscillators.