The circadian machinery links metabolic disorders and depression: A review of pathways, proteins and potential pharmacological interventions

Abstract

Circadian rhythms are responsible for regulating a number of physiological processes. The central oscillator is located within the suprachiasmatic nucleus (SCN) of the hypothalamus and the SCN synchronises the circadian clocks that are found in our peripheral organs through neural and humoral signalling. At the molecular level, biological clocks consist of transcription-translation feedback loops (TTFLs) and these pathways are influenced by transcription factors, post-translational modifications, signalling pathways and epigenetic modifiers. When disruptions occur in the circadian machinery, the activities of the proteins implicated in this network and the expression of core clock or clock-controlled genes (CCGs) can be altered. Circadian misalignment can also arise when there is desychronisation between our internal clocks and environmental stimuli. There is evidence in the literature demonstrating that disturbances in the circadian rhythm contribute to the pathophysiology of several diseases and disorders. This includes the metabolic syndrome and recently, it has been suggested that the 'circadian syndrome' may be a more appropriate term to use to not only describe the cardio-metabolic risk factors but also the associated comorbidities. Here we overview the molecular architecture of circadian clocks in mammals and provide insight into the effects of shift work, exposure to artificial light, food intake and stress on the circadian rhythm. The relationship between circadian rhythms, metabolic disorders and depression is reviewed and this is a topic that requires further investigation. We also describe how particular proteins involved in the TTFLs can be potentially modulated by small molecules, including pharmacological interventions and dietary compounds.

Keywords: Central circadian clock; Circadian rhythm; Clock proteins; Epigenetic modifications; Major depressive disorder; Metabolic disorders.