An astrocytic AMPK clock drives circadian behaviour

Abstract

Circadian clocks coordinate behaviour and physiology with daily cycles of light and nutrient availability, yet how metabolic signals tune brain timing remains unclear. Astrocytes integrate metabolic and hormonal cues and sustain cell-autonomous rhythms, implicating them as candidate links between energy state and central circadian control. Here we show that AMP-activated protein kinase (AMPK) in hypothalamic astrocytes exhibits intrinsic, calcium-dependent rhythmicity that persists under constant darkness and without feeding cues. This glial rhythm sustains time-of-day phosphorylation programmes in the hypothalamus and stabilises the clock protein PER2 via phosphorylation at a conserved serine residue, thereby linking metabolic state to period control beyond the canonical transcription-translation feedback loops. In the ventromedial hypothalamus, astrocytic AMPK-PER2 signalling is required for food-anticipatory activity, identifying a glial node within the food-entrainable timing system. Disrupting astrocytic AMPK rhythmicity alters circadian behaviour and energy homeostasis and shortens lifespan in a sex-dependent manner. These findings recast AMPK as a metabolically adaptive glial timekeeper that connects calcium signalling and phosphorylation rhythms to behaviour and metabolism. They also reveal a phosphorylation-based timing layer in central metabolic circuits, with implications for circadian-metabolic misalignment in contexts such as shift work and metabolic disorders.