Metabolism control by the circadian clock and vice versa

Abstract

Circadian rhythms govern a wide variety of physiological and metabolic functions in most organisms. At the heart of these regulatory pathways in mammals is the clock machinery, a remarkably coordinated transcription-translation system that relies on dynamic changes in chromatin states. Recent findings indicate that regulation also goes the other way, as specific elements of the clock can sense changes in cellular metabolism. Understanding in full detail the intimate links between cellular metabolism and the circadian clock machinery will provide not only crucial insights into system physiology but also new avenues toward pharmacological intervention of metabolic disorders.

Figure 1

The interplay between the circadian clock and cellular metabolism occurs at various levels. Central to cellular metabolism is the synthesis of NAD⁺, a process influenced by the circadian clock. Variable levels of NAD⁺ may influence numerous intracellular pathways. The small molecule cyclic ADP-ribose (cADPR) is produced from NAD⁺ by ADP-ribosyl cyclases and contributes to circadian oscillations in a ryanodine receptor (RyR)-dependent manner. Metabolites also have an attractive role in epigenetic control. NAD⁺ modulates the activity of chromatin-associated enzymes, such as PARP-1 and Sirt1. The activity of the NAD⁺-dependent histone deacetylase Sirt1 oscillates and participates in chromatin remodeling at circadian genes. There is no evidence to date for a circadian function of PARP-1, but its role in DNA damage repair and the reported interplay with Sirt1 (ref. 66) may be predictive of a circadian role. Finally, the central role of NAD⁺-activated mitochondrial proteins in energy metabolism begs the question of how they might contribute to circadian control. EdSumm: The mammalian circadian clock controls many biological functions, including metabolic activity. In this Perspective, the authors present recent literature and discuss the two-way relationship between the clock and metabolism, with NAD+ playing a central part in their integration.

Figure 2

By activating Sirt1, NAD⁺ conjoins two feedback loops necessary for cross-talk between the circadian clock and metabolite production. The NAD⁺-salvage pathway is important for regulating intracellular NAD⁺ levels. After the conversion of nicotinamide (NAM) into nicotinamide mononucleotide (NMN) by NAM phosphoribosyl transferase (NAMPT), NMN is further modified into NAD⁺ by the nicotinamide mononucleotide adenylyl transferases (Nmnat1,-2 and -3). Whereas NAM inhibits Sirt1 activity, NAD⁺-activated Sirt1 feeds back into the NAD⁺-salvage pathway by directly regulating Nampt gene expression in a Clock–Bmal1-dependent manner. By this mechanism, NAD⁺ conjoins the two feedback loops, contributing to the fine tuning necessary for achieving energy balance. EdSumm: The mammalian circadian clock controls many biological functions, including metabolic activity. In this Perspective, the authors present recent literature and discuss the two-way relationship between the clock and metabolism, with NAD+ playing a central part in their integration.