AMPK at the crossroads of circadian clocks and metabolism

Abstract

Circadian clocks coordinate behavior and physiology with daily environmental cycles and thereby optimize the timing of metabolic processes such as glucose production and insulin secretion. Such circadian regulation of metabolism provides an adaptive advantage in diverse organisms. Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1 and CRY2) proteins. Posttranslational modification of these core clock components is critical for setting clock time or adjusting the speed of the clock. AMP-activated protein kinase (AMPK) is one of several metabolic sensors that have been reported to transmit energy-dependent signals to the mammalian clock. AMPK does so by driving the phosphorylation and destabilization of CRY and PER proteins. In addition, AMPK subunit composition, sub-cellular localization, and substrate phosphorylation are dependent on clock time. Given the well-established role of AMPK in diverse aspects of metabolic physiology, the reciprocal regulation of AMPK and circadian clocks likely plays an important role in circadian metabolic regulation.

Figure 1. Core circadian clock machinery

Mammalian circadian clocks are based on a transcription and translation feedback loop in which the transcription factors CLOCK and its heterodimeric partner BMAL1 activate the transcription of genes encoding their own inhibitors, the period (PER1, PER2 and PER3) and cryptochrome (CRY1 and CRY2) repressor proteins.

Figure 2. AMPK phosphorylation motifs in clock proteins

Several proteins that are critical for the functioning of mammalian circadian clocks contain evolutionarily conserved sequences that may be preferentially phosphorylated by AMPK. Intriguingly, the AMPK-dependent phosporylation of cryptochromes seems to represent an evolutionary switch in which cryptochromes gained the ability to sense changes in chemical energy (ATP levels) rather than electromagnetic energy (light).

Figure 3. Metabolic inputs to the circadian core clock

A) AMPK phosphorylates CRY1 and CRY2, and targets them for degradation. AMPK has also been reported to phosphorylate CK1ε thereby increasing CK1ε activity and ultimately phosphorylation-mediated PER degradation. B) SIRT1 deacetylates BMAL1, PER2 and histone3 in a NAD+-dependent manner thus counteracting the histone-acetylase function of CLOCK. C) PARP1 poly ADP-ribosylates CLOCK in a NAD+-dependent reaction, which inhibits DNA binding by CLOCK-BMAL1. D) Nampt encodes for the rate-limiting enzyme in NAD+-synthesis and is regulated by CLOCK-BMAL1. The resulting circadian oscillations of NAD+ levels feed back on CLOCK-BMAL1 activity by affecting SIRT1 activity.