IMPAIRED ASTROCYTE PYRUVATE OXIDATION PROMOTES FATTY ACID OXIDATION VIA PRIMARY CILIA AND DIRECTS BRAIN NUTRIENT UPTAKE AND LIVER METABOLISM

Astrocytes sense and regulate brain fatty acid (FA) and glucose uptake and drive systemic adaptations to brain hypoglycaemia. Nutrient availability is detected in part through primary cilia (PC), which coordinate metabolic responses to stress. The role of astrocyte PC in metabolic rewiring and systemic control is unclear. Here, we investigated how chronic astrocyte starvation affects brain and whole-body metabolism and the role of PC in cellular adaptations.
In primary hypothalamic mouse astrocytes, PC morphology and ciliary gene expression changed dynamically with extracellular or intracellular substrate availability. Consistently, chronic high-fat diet (HFD) feeding altered PC morphology in GFAP+ astrocytes in the arcuate hypothalamus (ARH). To model chronic astrocyte starvation in vivo, we generated mice with inducible deletion of mitochondrial pyruvate carrier 1 (MPC1) in GFAP-expressing glia. MPC1 loss lengthened PC and triggered compensatory increases in glycolysis and FA oxidation.
Metabolic profiling of MPC-1^ΔGFAP mice showed reduced weight gain resulting from reduced food intake and a mild improvement in systemic glucose tolerance. MPC1 KD mice exhibited increased brain uptake of luciferin-tagged FA, enhanced activation of hypothalamic POMC neurons, and after 16 h fasting, increased brain glucose uptake with amplified hepatic fasting signals. Remarkably, providing saturated FA (palmitate) in vitro or HFD in vivo fully restored cellular, brain, and systemic phenotypes. Finally, the shift toward increased FAO upon MPC1 depletion required functional PC.
Overall, impaired astrocyte pyruvate metabolism improves systemic glucose homeostasis and induces a compensatory brain FA and glucose utilization. Astrocyte PC are essential for sensing cellular energetic status and metabolic rewiring.