Astrocytic AMPK couples metabolic signals to hypothalamic circadian timing

Circadian clocks coordinate behaviour and physiology with daily cycles of light and nutrient availability, but how metabolic signals influence brain timing remains incompletely understood. Astrocytes integrate metabolic and hormonal cues and exhibit time-of-day-dependent responses, suggesting that they may convey temporal information to hypothalamic circuits. Here, we show that hypothalamic AMP-activated protein kinase (AMPK) exhibits circadian regulation independently of light and feeding cues, is modulated by nutrient availability and astrocytic Ca{superscript 2} signalling, and regulates the temporal organisation of the hypothalamic phosphoproteome. Genetic manipulation of astrocytic AMPK signalling alters PER2 abundance and phosphorylation, including at a conserved residue implicated in circadian period regulation. At the behavioural level, AMPK and PER2 in ventromedial hypothalamic astrocytes contribute to food-anticipatory activity, whereas disruption of astrocytic AMPK signalling alters SCN-dependent circadian locomotor rhythms and energy homeostasis in a sex-dependent manner. Together, these findings identify astrocytic AMPK signalling as a temporally regulated pathway that couples metabolic signals to hypothalamic circadian timing and systemic homeostasis.