AMPK's Role in Circadian Rhythms
AMPK functions as a critical metabolic sensor that directly regulates the circadian clock machinery through phosphorylation of core clock proteins, with cellular AMP/ATP ratios driving AMPK activity to phosphorylate CRY1 and modulate its stability, thereby creating a bidirectional feedback loop between cellular energy status and circadian timekeeping. 1
Direct Molecular Mechanisms
AMPK directly phosphorylates circadian clock components to regulate their stability and function:
AMPK phosphorylates CRY1 (cryptochrome 1), a core negative regulator of the circadian clock, controlling its proteolytic degradation and thereby modulating the feedback inhibition of the CLOCK/BMAL1 transcriptional complex. 1, 2
AMPK also phosphorylates casein kinases (CKIα and CKIε), which are themselves critical regulators of PER protein stability—this creates a multi-layered regulatory network where AMPK influences both direct clock components and their upstream regulators. 2, 3
The activation state of AMPK is determined by cellular AMP/ATP ratios, meaning that metabolic status directly feeds back to regulate clock gene activity and stability through this energy-sensing mechanism. 1
Tissue-Specific Circadian Regulation
AMPK regulates circadian rhythms in an isoform- and tissue-specific manner, with distinct effects across metabolic organs:
The AMPKα1 isoform primarily regulates circadian rhythms in adipose tissue, with AMPKα1-deficient mice showing shorter circadian periods and dampened body temperature rhythms. 4
The AMPKα2 isoform predominantly controls circadian gene expression in heart and skeletal muscle, with AMPKα2-deficient mice exhibiting slightly longer circadian periods. 4
In liver tissue, AMPK activation leads to phase advances in clock and metabolic gene expression, while in muscle it causes phase delays—demonstrating that the same metabolic signal produces opposite temporal effects depending on tissue context. 3
Integration with NAD+ and SIRT1 Pathways
AMPK coordinates with NAD+-dependent pathways to synchronize metabolic and circadian oscillations:
AMPK regulates the circadian rhythm of NAMPT (nicotinamide phosphoribosyltransferase) activity, the rate-limiting enzyme converting nicotinamide to NAD+, which is itself a critical regulator of circadian clock function through SIRT1 activation. 4
The rhythm of NAMPT activity is absent in AMPK-deficient tissues and cells, demonstrating that AMPK is essential for maintaining the NAD+ oscillations that drive SIRT1-mediated deacetylation of CLOCK, BMAL1, and PER2. 1, 4
This creates a coordinated regulatory network where cellular energy status (sensed by AMPK) and redox state (sensed by NAD+/SIRT1) converge to regulate circadian timing. 2
Metabolic Feedback to the Clock
AMPK serves as a key node integrating feeding-fasting cycles with circadian clock function:
During fasting states when ATP production decreases, AMPK activation increases in an anti-phase relationship to ATP content—in retinal tissue, ATP peaks at early night while phosphorylated AMPK peaks during the day. 5
AMPK activation during fasting states leads to inhibition of anabolic processes (through ACC phosphorylation) while simultaneously adjusting clock gene expression to match the metabolic state. 3
High-fat diet feeding disrupts normal AMPK signaling patterns, leading to dampened clock gene expression and NAD+ rhythms—mathematical modeling predicts this can be pharmacologically rescued with timed REV-ERB agonist administration. 6
Downstream Signaling Integration
AMPK integrates into broader cell signaling networks to coordinate circadian physiology:
AMPK appears upstream of ERK (extracellular signal-regulated kinase) and mTORC1 (mammalian target of rapamycin complex 1) but downstream of adenylyl cyclase in regulating circadian-dependent cellular functions. 5
In photoreceptors, AMPK regulates the circadian rhythm of L-type voltage-gated calcium channels (L-VGCCs), with AMPK activation dampening L-VGCC currents at night and decreasing protein expression of the channel's pore-forming subunit. 5
This demonstrates that AMPK translates circadian timing information into functional changes in ion channel activity and neurotransmitter release patterns. 5
Clinical and Pharmacological Implications
Pharmacological AMPK activation affects circadian rhythms with tissue-specific temporal effects:
Metformin, which activates AMPK through LKB1 and other kinases, produces phase advances in liver clock genes but phase delays in muscle clock genes, demonstrating that the same drug produces opposite circadian effects in different tissues. 3
Redox-sensitive kinases including AMPK regulate circadian clock activity through phosphorylation of circadian proteins at different amino acids, making them potential therapeutic targets for circadian disruption. 1
The bidirectional relationship between AMPK and circadian clocks means that metabolic interventions (like time-restricted feeding) that normalize AMPK signaling patterns can restore circadian amplitude and synchronization across tissues. 1, 6
Coordination with Other Metabolic Sensors
AMPK works in concert with other nutrient-sensitive transcription factors to coordinate circadian gene expression:
Multiple metabolic sensors including O-GlcNAc glycosylation, NAD+-dependent PARPs and sirtuins, and oxygen-sensitive HIF1α all converge with AMPK signaling to regulate core clock components CLOCK, BMAL1, PER2, and CRY1. 1
This cooperation among nutrient-sensitive mechanisms ensures that circadian gene expression remains synchronized with daily cycling of nutrients and metabolic demands. 1
The system achieves compartmentalization of catabolic and anabolic processes throughout the day-night cycle to optimize energy homeostasis, with AMPK serving as a critical energy status checkpoint. 1