Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling

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.

A Double-Blind, Placebo-Controlled Trial Related to the Effects of Melatonin on Oxidative Stress and Inflammatory Parameters of Obese Women

“…During the past decade, several studies have supported the potential health benefits of melatonin including antioxidation, anti-inflammatory, immunomodulatory, body fat mass, and weight regulatory effects [10][11][12][13][24][25][26][27][28].…”

“…Melatonin (N-acetyl-5-methoxytryptamine) in mammals is synthesized in several cells, tissues, and organs mainly for local utilization (autocrine and paracrine actions) and the circulating melatonin is mostly provided by the pineal gland [11,12]. It is known that melatonin is responsible for regulation of circadian rhythms, immune responses and mood, and reduces oxidative stress [13][14][15][16]. The roles of melatonin in obesity management have been studied in animal models of diet-induced obesity.…”

Interactions of Melatonin and MicroRNAs

“…Regulatory interactions of melatonin with miRNAs are of particular interest as the former acts as a highly pleiotropic regulator molecule that orchestrates countless body functions, both directly and indirectly via central and peripheral circadian oscillators [15,16]. Circadian oscillators and even melatonin synthesis are also subject to modulation by miRNAs [2,[17][18][19].…”

The Underrated Circadian System and Its Contribution to Neurodegeneration in Mood Disorders

“…Because of its amplitude-enhancing properties, SIRT1 is of particular importance and, again, a polymorphism in the Sirt1 gene was demonstrated in MDD 48 . Additionally, polymorphisms of Per1 and Clock or Per1 and Npas2 were found to be associated with other behavioral disorders, such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), respectively 46 . Collectively, these data strongly support a contribution of deviations in the circadian system to the etiologies of mood disorders.…”