Astroglial aerobic glycolysis, a process during which d-glucose is converted to l-lactate, a brain fuel and signal, is regulated by the plasmalemmal receptors, including adrenergic receptors (ARs) and purinergic receptors (PRs), modulating intracellular Ca²⁺ and cAMP signals. However, the extent to which the two signals regulate astroglial aerobic glycolysis is poorly understood. By using agonists to stimulate intracellular α₁-/β-AR-mediated Ca²⁺/cAMP signals, β-AR-mediated cAMP and P₂R-mediated Ca²⁺ signals and genetically encoded fluorescence resonance energy transfer-based glucose and lactate nanosensors in combination with real-time microscopy, we show that intracellular Ca²⁺, but not cAMP, initiates a robust increase in the concentration of intracellular free d-glucose ([glc]_i) and l-lactate ([lac]_i), both depending on extracellular d-glucose, suggesting Ca²⁺-triggered glucose uptake and aerobic glycolysis in astrocytes. When the glycogen shunt, a process of glycogen remodelling, was inhibited, the α₁-/β-AR-mediated increases in [glc]_i and [lac]_i were reduced by ∼65 % and ∼30 %, respectively, indicating that at least ∼30 % of the utilization of d-glucose is linked to glycogen remodelling and aerobic glycolysis. Additional activation of β-AR/cAMP signals aided to α₁-/β-AR-triggered [lac]_i increase, whereas the [glc]_i increase was unaltered. Taken together, an increase in intracellular Ca²⁺ is the prime mechanism of augmented aerobic glycolysis in astrocytes, while cAMP has only a moderate role. The results provide novel information on the signals regulating brain metabolism and open new avenues to explore whether astroglial Ca²⁺ signals are dysregulated and contribute to neuropathologies with impaired brain metabolism.

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