Given the fundamental importance of the circadian system in mammalian physiology, circadian rhythmicity permeates all levels of mammalian organization from behavior to hormonal secretion, temperature regulation, as well as molecular regulation of gene transcription and translation 日内変動をリズムよくすることは臓器内の遺伝子の働きをよくします

To provide efficient and precise coordination of circadian timing throughout the body, the circadian system is organized as a multi-level hierarchical oscillator network 

The pacemaker or “master clock” is localized to a subset of bilateral neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus .　日内変動のペースメ－カ－である時計は視床下部の視交叉上核にあります

Indeed, SCN neurons appear to determine the period of an organism’s circadian rhythms and are essential for the generation of circadian rhythms in most physiological and behavioral functions .

日光は最も大事な時計合わせをする刺激です

Light is the most salient stimulus responsible for the entrainment of the SCN clock to daily changes in LD cycles 

Entrainment of the SCN clock to environmental cycles is mediated via direct retinal projections from the specialized melanopsin-enriched photoreceptors

. It is important to note that light-mediated circadian neuronal pathways are distinct from conventional phototransduction mediated by rods and cones, which further emphasizes the unique nature of the circadian system in mammalian physiology (36).

In recent years, an increased emphasis has been placed on the development of small-molecule chemical enhancers of circadian system with goals of augmenting clock-regulated physiological outputs . Subsequently, a number of chemical compounds specifically targeting the core circadian oscillator have been developed with documented efficacy in modulating metabolic function in pre-clinical studies.

Specifically, Nobiletin (a naturally occurring flavonoid) has been recently identified as a clock amplitude enhancer, actions of which are mediated through ROR nuclear receptor activation . Importantly, chronic administration of Nobiletin in two distinct obese/T2DM mouse models resulted in restoration of oscillatory patterns in circadian and metabolic gene expression in the liver and corresponding phenotypical improvements in glycemia, glucose tolerance, insulin resistance, and ectopic fat accumulation .

ノビレチンによって各臓器にある代謝リズム同調機が活性化できるかもしれない

Another recently discovered chemical modulator of the circadian system, Rev-ERB-α/β agonist, also has been shown to modulate circadain metabolic gene expression and improve glycemia, lipidemia, and ectopic fat accumulation in mice (149). Moreover, Hirota and colleagues identified a small molecule CRY activator (KL001) that interferes with ubiquitin-mediated CRY degradation, resulting in CRY stabilization and lengthening of the circadain period (49). Importantly, KL001 administration was shown to attenuate glucagon-induced gluconeogenic flux in isolated hepatocytes in vitro and also to improve glucose intolerance in obese insulin-resistant mice in vivo (49, 52). Finally, beneficial metabolic effects ascribed to chemical modulators of Rev-ERB-α/β and CRY were not associated with enhanced circadian clock amplitude, which underscores that more studies are needed to fully understand mechanisms underlying physiological effects of clock-modifying chemical compounds (49, 52).