Metabolic changes play a critical role in brain plasticity and cognitive function. For many years, glucose was considered the main energy fuel for the brain. However emerging evidence suggests that astrocytes engage in active fatty acid oxidation (FAO). Despite this, our understanding of the regulatory mechanisms governing FAO - and how they are disrupted in pathological conditions - remains limited. In this thesis, we characterize astrocytic FAO and investigate its regulation by glutamate, indicative of neuronal activity. Using brain slices, we demonstrate active FAO, and we further employ primary cultures of astrocytes, neurons, microglia, and neuron-astrocyte co-cultures to explore the underlying molecular pathways. Our results confirm that FAO and glucose metabolism coexist in astrocytes. We also provide evidence that glutamate tunes down reversibly FAO and oxygen consumption, thereby increasing local oxygen availability. No significant differences in FAO activity were observed among astrocytes from different brain regions or between sexes. We show that FAO inhibition involves glutamate transporters but not the activation of glutamate metabotropic, NMDA or AMPA receptors. Additionally, glutamate reduces mitochondrial membrane potential and increases the NADH/NAD+ ratio, indicating impaired electron transport. Remarkably, both glutamate and aspartate inhibit FAO in human astrocytes via a mechanism dependent on the glutamate transporter EAAT, whereas carnitine potentiates this metabolic pathway. As a first step toward understanding the consequences of FAO modulation and the glutamate-induced metabolic adaptation in astrocytes and brain physiology, we show that glutamate induces Drp1-mediated mitochondrial fission and promotes astrocytic survival, in contrast to neurons where it induces excitotoxicity. Furthermore, FAO inhibition modulates purinergic-induced calcium responses in astrocytes, key events for neuron-astrocyte communication. In summary, our results offer new conceptual and mechanistic insights into astrocytic oxidative metabolism and represent a significant step forward in understanding the metabolic interactions between astrocytes and neurons.
Study of mitochondrial fatty acid oxidation in the brain and the mechanisms underlying its inhibition by glutamate in astrocytes
Bagur Llufriu, F. J. (Author). 7 Nov 2025
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis