Transcriptomic and metabolic signatures of neural cells cultured under a physiologic-like environment.

Cultured brain cells are used conventionally to investigate fundamental neurobiology and identify therapeutic targets against neural diseases. However, standard culture conditions do not simulate the natural cell microenvironment, thus hampering in vivo translational insight. Major weaknesses include atmospheric (21%) O tension and lack of intercellular communication, the two factors likely impacting metabolism and signaling.

Weak neuronal glycolysis sustains cognition and organismal fitness.

The energy cost of neuronal activity is mainly sustained by glucose. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase-3 (PFKFB3), a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression.

Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.

Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them to fulfil their own energy needs and deliver metabolic intermediates to local synapses. These glial cells should be, therefore, metabolically adaptable to swap different substrates. However, in vitro and in vivo studies consistently show that astrocytes are primarily glycolytic, suggesting glucose is their main metabolic precursor.

Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling.

Ketone bodies are metabolites that replace glucose as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting, extenuating exercise, or pathological conditions such as diabetes. Beyond their role as an alternative fuel for the brain, the impact of ketone bodies on neuronal physiology has been highlighted by the use of the so-called "ketogenic diets," which were proposed about a century ago to treat infantile seizures. These diets mimic fasting by reducing drastically the intake of carbohydrates and proteins and replacing them with fat, thus promoting ketogenesis.