Elucidating reaction dynamics in a model of human brain energy metabolism

Influence of birth on carbohydrate and energy metabolism in rat brain.

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Fetal growth restriction (FGR) remains a cause of perinatal brain injury, sometimes leading to neurological and intellectual impairment. Although the mechanisms and pathophysiology of CNS injuries have not been elucidated completely, it is possible carbohydrate and energy metabolism may have an important role in the FGR brain. In this study, FGR was induced in rats by administration of synthetic thromboxane A2 (STA2). Pups were delivered by cesarean section. After killing, samples were obtained from the fetuses of both control and FGR rats for evaluation of carbohydrate and energy metabolism in brain tissue. Lactate and pyruvate levels in brain were reduced significantly in the FGR group. Glucose content in brain tissue tended to be increased in the FGR group. In contrast, glycogen content in brain tissue tended to be lower in the FGR group. However, these differences in glucose and glycogen content did not reach statistical significance. Brain high-energy reserves, including ATP, ADP, AMP, and phosphocreatine (P-Cr), were similar in the control and FGR groups. Gluconeogenesis compensated for chronic fetal hypoxia and decreased glycogen storage. Energy metabolism in the FGR brain is likely to be disrupted as a consequence of lower reserves of energy substrates.

Proper regulation of energy metabolism in the brain is crucial for maintaining brain activity in physiological and different pathophysiological conditions. Ischemic stroke has a complex pathophysiology which includes perturbations in the brain energy metabolism processes which can contribute to worsening of brain injury and stroke outcome. Smoking and diabetes are common risk factors and comorbid conditions for ischemic stroke which have also been associated with disruptions in brain energy metabolism. Simultaneous presence of these conditions may further alter energy metabolism in the brain leading to a poor clinical prognosis after an ischemic stroke event. In this review, we discuss the possible effects of smoking and/or diabetes on brain glucose utilization and mitochondrial energy metabolism which, when present concurrently, may exacerbate energy metabolism in the ischemic brain. More research is needed to investigate brain glucose utilization and mitochondrial oxidative metabolism in ischemic stroke in the presence of smoking and/or diabetes, which would provide further insights on the pathophysiology of these comorbid conditions and facilitate the development of therapeutic interventions.

Brain (cerebral) blood flow (CBF) and metabolism have long been subjects of great interest, but progress in their study awaited development of quantitative methods applicable to unanesthetized animals and man. The development of the nitrous oxide method by Kety and Schmidt (1948) revolutionized the field and led to much of our present knowledge of the physiology and pharmacology of CBF and energy metabolism in humans in health and disease. This method, however, measured only average CBF in the whole brain. This limitation was overcome by development of the autoradiographic [131I]trifluoroiodomethane (CF,131I) method by Kety and colleagues that measured local CBF simultaneously in all structures of the brain in conscious animals. Its autoradiograms provided visual images of the relative rates of CBF and led to the first demonstration of functional brain imaging (i.e., increases in CBF in structures of the cat visual system during retinal stimulation). The CF3 131I method was later modified for use with 14C autoradiography and a nonvolatile tracer, first[14C]antipyrine and then [14C]iodoantipyrine. This is the same method that was later adapted for use in humans with H2 15O and positron emission tomography (PET) and is now commonly used. The CF3 131I method and its derivatives were applied during uptake of tracer by cerebral tissues, but its basic principles apply equally well to clearance of the tracer from tissues. In 1949 Kety had reported a technique to determine local muscle blood flow by clearance of 24Na injected into the tissue. This method was modified for use with radioactive gases, first 85Kr and then 133Xe, both of which freely cross the blood-brain barrier, and this clearance method has been used to measure regional CBF at rest and during alteration in local functional activity in humans. Energy metabolism is a function of individual cells, but CBF serves regions of the brain and is sensitive to systemic factors (e.g., blood gas tensions, pH). Measurement of local energy metabolism could therefore be expected to provide better resolution and specificity in response to altered neuronal functional activity. Sokoloff and coworkers, employing quantitative autoradiography together with radioactive 2-deoxy-n-glucose (2-DG), developed a method to measure local cerebral glucose utilization (1CMRglc). They applied this method to localize and image local alterations in functional neuronal activity on the basis of changes in 1CMRglc in many physiological, pharmacological, and pathological states and used it to define and quantify the relations between energy metabolism and functional and electrical activities in neural tissues. Because it employed autoradiography, the 2-DG method could not be used in humans. Therefore, Reivich and coworkers (1979) adapted the method for use in humans with Kuhl’s Mark IV single photon section scanner and the remitting analogue of 2-DG, 2-deoxy-2-[18F]fluoro-D-glucose 18FDG).18F is a positron emitter; and soon afterward Phelps, Kuhl, and coworkers (1979) modified the 18FDG method for use with PET with its superior spatial resolution and quantification. This method has been widely used to study regional energy metabolism in brain and other organs in humans in health and disease. Magnetic resonance imaging (MRI) techniques that provide signals correlating with changes in local CBF have recently been developed. These techniques measure increase in proton signal that occur when paramagnetic deoxyhemoglobin levels are reduced in the region of interest. Because CBF transiently increases more than O2 consumption when brain tissue is activated, the venous deoxyhemoglobin content is reduced, and the enhancement in local proton signal is displayed in computer-generated reconstructed images. It should be noted that any cause of arterial vasodilatation, even if blood flow is not increased (e.g., during autoregulatory response to hypotension), reduces venous blood and deoxyhemoglobin contents in accordance with the principles of the Munro-Kellie doctrine. Nevertheless, MRIbased functional brain imaging has become the most popular CBF-related technique in use today because of its noninvasiveness, lack of ionizing radiation, excellent spatial and temporal resolution, and repeatability. Although it may correlate with changes in CBF, however, it does not measure it.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Its etiology and associated mechanisms are still unclear, which largely hinders the development of AD treatment strategies. Many studies have shown that dysregulation of energy metabolism in the brain of AD is closely related to disease development. Dysregulation of brain energy metabolism in AD brain is associated with reduced glucose uptake and utilization, altered insulin signaling pathways, and mitochondrial dysfunction. In this study, we summarized the relevant pathways and mechanisms regarding the dysregulation of energy metabolism in AD. In addition, we highlight the possible role of mitochondrial dysfunction as a central role in the AD process. A deeper understanding of the relationship between energy metabolism dysregulation and AD may provide new insights for understanding learning memory impairment in AD patients and in improving AD prevention and treatment.

Effect of photic stimulation (PS) on energy metabolism in the human occipital cortex was examined by using phosphorus-31 magnetic resonance spectroscopy in 9 normal subjects. Phosphocreatine (PCr)/total phosphorus signal peak area ratio significantly decreased from 12.3% to 10.9% during the 12 minutes of PS (P < 0.05). PCr once returned to a normal level after PS (11.9%) but significantly decreased again 12-18 minutes after PS (10.8%; P < 0.05). Intracellular pH increased from 7.08 to 7.16 during PS, although this increase was not significant. These results suggest that functional alteration of energy metabolism in the brain is different from that in muscles.

Do active cerebral neurons really use lactate rather than glucose?

Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.

Processing of incoming sensory stimulation triggers an increase of cerebral perfusion and blood oxygenation (neurovascular response) as well as an alteration of the metabolic neurochemical profile (neurometabolic response). Here, we show in human primary visual cortex (V1) that perceived and unperceived isoluminant chromatic flickering stimuli designed to have similar neurovascular responses as measured by blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) have markedly different neurometabolic responses as measured by proton functional magnetic resonance spectroscopy (1H-fMRS). In particular, a significant regional buildup of lactate, an index of aerobic glycolysis, and glutamate, an index of malate–aspartate shuttle, occurred in V1 only when the flickering was perceived, without any relation with other behavioral or physiological variables. Whereas the BOLD-fMRI signal in V1, a proxy for input to V1, was insensitive to flickering perception by design, the BOLD-fMRI signal in secondary visual areas was larger during perceived than unperceived flickering, indicating increased output from V1. These results demonstrate that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1, and that 1H-fMRS provides unique information about local input/output balance that is not measured by BOLD-fMRI.

The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.

Cerebral function is associated with exceptionally high metabolic activity, and requires continuous supply of oxygen and nutrients from the blood stream. Since the mid-twentieth century the idea that brain energy metabolism is coupled to neuronal activity has emerged, and a number of studies supported this hypothesis. Moreover, brain energy metabolism was demonstrated to be compartmentalized in neurons and astrocytes, and astrocytic glycolysis was proposed to serve the energetic demands of glutamatergic activity. Shedding light on the role of astrocytes in brain metabolism, the earlier picture of astrocytes being restricted to a scaffold-associated function in the brain is now out of date. With the development and optimization of non-invasive techniques, such as nuclear magnetic resonance spectroscopy (MRS), several groups have worked on assessing cerebral metabolism in vivo. In this context, 1H MRS has allowed the measurements of energy metabolism-related compounds, whose concentrations can vary under different brain activation states. 1H-[13C] MRS, i.e., indirect detection of signals from 13C-coupled 1H, together with infusion of 13C-enriched glucose has provided insights into the coupling between neurotransmission and glucose oxidation. Although these techniques tackle the coupling between neuronal activity and metabolism, they lack chemical specificity and fail in providing information on neuronal and glial metabolic pathways underlying those processes. Currently, the improvement of detection modalities (i.e., direct detection of 13C isotopomers), the progress in building adequate mathematical models along with the increase in magnetic field strength now available render possible detailed compartmentalized metabolic flux characterization. In particular, direct 13C MRS offers more detailed dataset acquisitions and provides information on metabolic interactions between neurons and astrocytes, and their role in supporting neurotransmission. Here, we review state-of-the-art MR methods to study brain function and metabolism in vivo, and their contribution to the current understanding of how astrocytic energy metabolism supports glutamatergic activity and cerebral function. In this context, recent data suggests that astrocytic metabolism has been underestimated. Namely, the rate of oxidative metabolism in astrocytes is about half of that in neurons, and it can increase as much as the rate of neuronal metabolism in response to sensory stimulation.

Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids

Experimental evidence that ornithine and homocitrulline disrupt energy metabolism in brain of young rats

Apolipoprotein-B100 (apoB100) is the essential protein for the assembly and secretion of very low density lipoproteins (VLDL) from liver. The hepatoma HepG2 cell line has been the cell line of choice for the study of synthesis and secretion of human apoB-100. Despite the general use of HepG2 cells to study apoB100 metabolism, they secrete relatively dense, lipid-poor particles compared with VLDL secreted in vivo. Recently, Huh-7 cells were adopted as an alternative model to HepG2 cells, with the implicit assumption that Huh-7 cells were superior in some respects of lipoprotein metabolism, including VLDL secretion. In this study we addressed the hypothesis that the spectrum of apoB100 lipoprotein particles secreted by Huh-7 cells more closely resembles the native state in human liver. We find that Huh-7 cells resemble HepG2 cells in the effects of exogenous lipids, microsomal triglyceride transfer protein (MTP)-inhibition, and proteasome inhibitors of apoB100 secretion, recovery, and degradation. In contrast to HepG2 cells, however, MEK-ERK inhibition does not correct the defect in VLDL secretion. Huh-7 cells do not appear to offer any advantages over HepG2 cells as a general model of human apoB100-lipoprotein metabolism.