The metabolic significance of peripheral tissue clocks

Abstract

The circadian clock is a transcriptional-translational feedback loop which oscillates in virtually all nucleated cells of the body. In the decades since its discovery, it has become evident that the molecular clockwork is inextricably linked to energy metabolism. Given the frequency with which metabolic dysfunction and clock disruption co-occur, understanding why and how clock and metabolic processes are reciprocally coupled will have important implications for supporting human health and wellbeing. Here, we discuss the relevance of molecular clock function in metabolic tissues and explore its role not only as a driver of day-night variation in gene expression, but as a key mechanism for maintaining metabolic homeostasis in the face of fluctuating energy supply and demand.

Fig. 1. Organisation of the circadian clock.

The suprachiasmatic nucleus (SCN) of the hypothalamus receives light/dark cues via the retinal-hypothalamic tract. The core molecular clock oscillates in nucleated cells of both the SCN and peripheral tissues (e.g. pancreas, adipose, liver, skeletal muscle, heart); this is a transcriptional-translational feedback loop (TTFL) that cycles with a 24-h period. The CLOCK:BMAL1 heterodimer promotes the expression of repressive CRYPTOCHROME (CRY) and PERIOD (PER) proteins, which prevent further CLOCK:BMAL1-mediated transcriptional activation. CLOCK:BMAL1 also promote the expression of activator ROR and repressor REV-ERB proteins, which compete at gene regulatory elements, including those regulating core clock gene expression. Peripheral tissues are responsive to systemic signals from both the SCN and other organs and are capable of feeding back to the brain. Image created using elements from NIH BIOART^–.

Fig. 2. Factors contributing to observed metabolic rhythms.

The SCN and central nervous system direct rhythms in behaviour (e.g. feeding), in circulating endocrine signals (e.g. glucocorticoids (GCs)), and in autonomic signalling (sympathetic and parasympathetic nervous systems (SNS, PNS)). Combined with dynamic signals derived from the environment, these systemic cues influence observed rhythms in metabolic processes.

Fig. 3. A model of local clock action.

The role of the tissue clock is to gate the activity of rhythmic physiological processes, which are ultimately driven by central cues. This may be through suppressing or amplifying the influence of behaviour-driven systemic signals. This may arise through modulation of key metabolic regulators (e.g. PDK4, which phosphorylates pyruvate dehydrogenase), or through regulation of the transcriptional response to metabolic state change. Image created using an element from NIH BIOART.