16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice.

Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

Voluntary Behavior and Training Conditions Modulate in vivo Extracellular Glucose and Lactate in the Mouse Primary Motor Cortex.

Learning or performing new behaviors requires significant neuronal signaling and is metabolically demanding. The metabolic cost of performing a behavior is mitigated by exposure and practice which result in diminished signaling and metabolic requirements. We examined the impact of novel and habituated wheel running, as well as effortful behaviors on the modulation of extracellular glucose and lactate using biosensors inserted in the primary motor cortex of mice. We found that motor behaviors produce increases in extracellular lactate and decreases in extracellular glucose in the primary motor cortex. These effects were modulated by experience, novelty and intensity of the behavior. The increase in extracellular lactate appears to be strongly associated with novelty of a behavior as well as the difficulty of performing a behavior. Our observations are consistent with the view that a main function of aerobic glycolysis is not to fuel the current neuronal activity but to sustain new bio-infrastructure as learning changes neural networks, chiefly through the shuttling of glucose derived carbons into the pentose phosphate pathway for the biosynthesis of nucleotides.

Brain and muscle adaptation to high-fat diets and exercise: Metabolic transporters, enzymes and substrates in the rat cortex and muscle.

There is evidence suggesting that the effects of diet and physical activity on physical and mental well-being are the result of altered metabolic profiles. Though the central and peripheral systems work in tandem, the interactions between peripheral and central changes that lead to these altered states of well-being remains elusive. We measured changes in the metabolic profile of brain (cortex) and muscle (soleus and plantaris) tissue in rats following 5-weeks of treadmill exercise and/or a high-fat diet to evaluate peripheral and central interactions as well as identify any common adaptive mechanisms. To characterize changes in metabolic profiles, we measured relative changes in key metabolic enzymes (COX IV, hexokinase, LDHB, PFK), substrates (BHB, FFA, glucose, lactate, insulin, glycogen, BDNF) and transporters (MCT1, MCT2, MCT4, GLUT1, GLUT3). In the cortex, there was an increase in MCT1 and a decrease in glycogen following the high-fat diet, suggesting an increased reliance on monocarboxylates. Muscle changes were dependent muscle type. Within the plantaris, a high-fat diet increased the oxidative capacity of the muscle likely supported by increased glycolysis, whereas exercise increased the oxidative capacity of the muscle likely supported via increased glycogen synthesis. There was no effect of diet on soleus measurements, but exercise increased its oxidative capacity likely fueled by endogenous and exogenous monocarboxylates. For both the plantaris and soleus, combining exercise training and high-fat diet mediated results, resulting in a middling effect. Together, these results indicate the variable adaptions of two main metabolic pathways: glycolysis and oxidative phosphorylation. The results also suggest a dynamic relationship between the brain and body.

Fluctuations of extracellular glucose and lactate in the mouse primary visual cortex during visual stimulation.

We measured the extracellular glucose and lactate in the primary visual cortex in the CD-1 mouse using electrochemical electrodes. To gain some additional information on brain metabolism, we examined the impact of systemic injections of lactate and fructose on the brain extracellular glucose and lactate changes observed during visual stimulation. We found that simple stimulation using a flashlight produced a decrease in visual cortex extracellular glucose and an increase in extracellular lactate. Similar results were observed following visual stimulation with an animated movie without soundtrack or the presentation of a novel object. Specificity of these observations was confirmed by the absence of extracellular glucose and lactate changes when the mice were presented a second time with the same object. Previous experiments have shown that systemic injections of fructose and lactate lead to an increase in blood lactate but no change in blood glucose while they both increase brain extracellular glucose but they do not increase brain extracellular lactate. When mice were visually stimulated after they had received these injections, we found that lactate, and to a slightly lesser degree fructose, both reduced the amplitude of the changes in extracellular glucose and lactate that accompanied visual stimulation. Thus, neural activation leads to an increase in extracellular lactate and a decrease in extracellular glucose. Novelty, attentional resources and availability of metabolic fuels modulate these fluctuations. The observations are consistent with a modified view of brain metabolism that takes into account the blood and brain glucose availability.

Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse.

Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved.