Brain energy metabolism adenosine mediated cAMP signaling in astrocytes.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Xevo TQ-S
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Virag Sagi-Kiss
PROVIDER: MSV000094445 | MassIVE | Mon Apr 01 08:51:00 BST 2024
REPOSITORIES: MassIVE
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2024-04-01 | MSV000094445 | GNPS
Project description:Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20-25% of the whole body's energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer's disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.
| S-EPMC8787066 | biostudies-literature
Project description:Most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons and non-neuronal cells, including astrocytes, which metabolically support neurons with nutrients. Neuronal metabolism largely depends on the activation of the noradrenergic system releasing noradrenaline. Activation of astroglial adrenergic receptors with noradrenaline triggers cAMP and Ca2+ signaling and augments aerobic glycolysis with production of lactate, an important neuronal energy fuel. Astrocytes with cytoplasmic TDP-43 inclusions can cause motor neuron death, however, whether astroglial metabolism and metabolic support of neurons is altered in astrocytes with TDP-43 inclusions, is unclear. We measured lipid droplet and glucose metabolisms in astrocytes expressing the inclusion-forming C-terminal fragment of TDP-43 or the wild-type TDP-43 using fluorescent dyes or genetically encoded nanosensors. Astrocytes with TDP-43 inclusions exhibited a 3-fold increase in the accumulation of lipid droplets versus astrocytes expressing wild-type TDP-43, indicating altered lipid droplet metabolism. In these cells the noradrenaline-triggered increases in intracellular cAMP and Ca2+ levels were reduced by 35% and 31%, respectively, likely due to the downregulation of β2-adrenergic receptors. Although noradrenaline triggered a similar increase in intracellular lactate levels in astrocytes with and without TDP-43 inclusions, the probability of activating aerobic glycolysis was facilitated by 1.6-fold in astrocytes with TDP-43 inclusions and lactate MCT1 transporters were downregulated. Thus, while in astrocytes with TDP-43 inclusions noradrenergic signaling is reduced, aerobic glycolysis and lipid droplet accumulation are facilitated, suggesting dysregulated astroglial metabolism and metabolic support of neurons in TDP-43-associated ALS and FTD.
| S-EPMC7138839 | biostudies-literature
Project description:RNA-binding proteins are key players in coordinated post-transcriptional regulation of functionally related genes, defined as RNA regulons. RNA regulons play particularly critical roles in parasitic trypanosomes, which exhibit unregulated co-transcription of long unrelated gene arrays. In this report, we present a systematic analysis of an essential RNA-binding protein, RBP42, in the mammalian-infective bloodstream form of African trypanosome, and show that RBP42 is a key regulator of parasite’s central carbon and energy metabolism. Using individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) to identify genome-wide RBP42-RNA interactions, we show that RBP42 preferentially binds within the coding region of mRNAs encoding core metabolic enzymes. Global quantitative transcriptomic and proteomic analyses reveal that loss of RBP42 reduces the abundance of target mRNA-encoded proteins, but not target mRNA, suggesting a positive translational regulatory role of RBP42. Significant changes in central carbon metabolic intermediates, following loss of RBP42, further support its critical role in cellular energy metabolism.
2021-06-11 | PXD026622 | Pride
Project description:UNLABELLED:Astrocytes are well established modulators of extracellular glutamate, but their direct influence on energy balance-relevant behaviors is largely understudied. As the anorectic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists are partly mediated by central modulation of glutamatergic signaling, we tested the hypothesis that astrocytic GLP-1R signaling regulates energy balance in rats. Central or peripheral administration of a fluorophore-labeled GLP-1R agonist, exendin-4, localizes within astrocytes and neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus critical for energy balance control. This effect is mediated by GLP-1R, as the uptake of systemically administered fluorophore-tagged exendin-4 was blocked by central pretreatment with the competitive GLP-1R antagonist exendin-(9-39). Ex vivo analyses show prolonged exendin-4-induced activation (live cell calcium signaling) of NTS astrocytes and neurons; these effects are also attenuated by exendin-(9-39), indicating mediation by the GLP-1R. In vitro analyses show that the application of GLP-1R agonists increases cAMP levels in astrocytes. Immunohistochemical analyses reveal that endogenous GLP-1 axons form close synaptic apposition with NTS astrocytes. Finally, pharmacological inhibition of NTS astrocytes attenuates the anorectic and body weight-suppressive effects of intra-NTS GLP-1R activation. Collectively, data demonstrate a role for NTS astrocytic GLP-1R signaling in energy balance control. SIGNIFICANCE STATEMENT:Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are approved by the Food and Drug Administration for the treatment of obesity, but the cellular mechanisms underlying the anorectic effects of GLP-1 require further investigation. Astrocytes represent a major cellular population in the CNS that regulates neurotransmission, yet the role of astrocytes in mediating energy balance is largely unstudied. The current data provide novel evidence that astrocytes within the NTS are relevant for energy balance control by GLP-1 signaling. Here, we report that GLP-1R agonists activate and internalize within NTS astrocytes, while behavioral data suggest the pharmacological relevance of NTS astrocytic GLP-1R activation for food intake and body weight. These findings support a previously unknown role for CNS astrocytes in energy balance control by GLP-1 signaling.
| S-EPMC4804010 | biostudies-literature
Project description:GSK3? is a serine threonine kinase implicated in the progression of Alzheimer's disease. Although the role of GSK3? in growth and pathology has been extensively studied, little is known about the metabolic consequences of GSK3? manipulation, particularly in the brain. Here, we show that GSK3? regulates mitochondrial energy metabolism in human H4 neuroglioma cells and rat PC12-derived neuronal cells and that inhibition of GSK3? in mice in vivo alters metabolism in the hippocampus in a region-specific manner. We demonstrate that GSK3? inhibition increases mitochondrial respiration and membrane potential and alters NAD(P)H metabolism. These metabolic effects are associated with increased PGC-1? protein stabilization, enhanced nuclear localization, and increased transcriptional co-activation. In mice treated with the GSK3? inhibitor lithium carbonate, changes in hippocampal energy metabolism are linked to increased PGC-1?. These data highlight a metabolic role for brain GSK3? and suggest that the GSK3?/PGC-1? axis may be important in neuronal metabolic integrity.
| S-EPMC6082412 | biostudies-other
Project description:Diatoms are responsible for ~40% of marine primary productivity1, fueling the oceanic carbon cycle and contributing to natural carbon sequestration in the deep ocean2. Diatoms rely on energetically expensive carbon concentrating mechanisms (CCMs) to fix carbon efficiently at modern levels of CO23–5. How diatoms may respond over the short and long-term to rising atmospheric CO2 remains an open question. Here we use nitrate-limited chemostats to show that the model diatom Thalassiosira pseudonana rapidly responds to increasing CO2 by differentially expressing gene clusters that regulate transcription and chromosome folding and subsequently reduces transcription of photosynthesis and respiration gene clusters under steady-state elevated CO2. These results suggest that exposure to elevated CO2 first causes a shift in regulation and then a metabolic rearrangement. Genes in one CO2-responsive cluster included CCM and photorespiration genes that share a putative cyclic-AMP responsive cis-regulatory sequence, implying these genes are co-regulated in response to CO2 with cAMP as an intermediate messenger. We verified cAMP-induced down-regulation of CCM gene δ-CA3 in nutrient-replete diatom cultures by inhibiting the hydrolysis of cAMP. These results indicate an important role for cAMP in down-regulating CCM and photorespiration genes under elevated CO2 and provide insights into mechanisms of diatom acclimation in response to climate change.
2015-04-17 | GSE67971 | GEO
Project description:Coordinated metabolism of carbon and nitrogen is essential for optimal plant growth and development. Nitrate is an important molecular signal for plant adaptation to changing environmental conditions, but how nitrate regulates plant growth under carbon deficiency conditions remains unclear. Here, we show that the evolutionarily conserved energy sensor SnRK1 negatively regulates the nitrate signaling pathway. Nitrate promoted plant growth and downstream gene expression, but such effects were significantly repressed when plants were grown under carbon deficiency conditions. Mutation of KIN10, the α-catalytic subunit of SnRK1, partially suppressed the inhibitory effects of carbon deficiency on nitrate-mediated plant growth. KIN10 phosphorylated NLP7, the master regulator of nitrate signaling pathway, to promote its cytoplasmic localization and degradation. Furthermore, nitrate depletion induced KIN10 accumulation, whereas nitrate treatment promoted KIN10 degradation. Such KIN10-mediated NLP7 regulation allows carbon and nitrate availability to control the optimal nitrate signaling and ensures the coordination of carbon and nitrogen metabolism in plants.
2022-07-23 | GSE206841 | GEO
Project description:Diatoms are responsible for ~40% of marine primary productivity1, fueling the oceanic carbon cycle and contributing to natural carbon sequestration in the deep ocean2. Diatoms rely on energetically expensive carbon concentrating mechanisms (CCMs) to fix carbon efficiently at modern levels of CO23–5. How diatoms may respond over the short and long-term to rising atmospheric CO2 remains an open question. Here we use nitrate-limited chemostats to show that the model diatom Thalassiosira pseudonana rapidly responds to increasing CO2 by differentially expressing gene clusters that regulate transcription and chromosome folding and subsequently reduces transcription of photosynthesis and respiration gene clusters under steady-state elevated CO2. These results suggest that exposure to elevated CO2 first causes a shift in regulation and then a metabolic rearrangement. Genes in one CO2-responsive cluster included CCM and photorespiration genes that share a putative cyclic-AMP responsive cis-regulatory sequence, implying these genes are co-regulated in response to CO2 with cAMP as an intermediate messenger. We verified cAMP-induced down-regulation of CCM gene ?-CA3 in nutrient-replete diatom cultures by inhibiting the hydrolysis of cAMP. These results indicate an important role for cAMP in down-regulating CCM and photorespiration genes under elevated CO2 and provide insights into mechanisms of diatom acclimation in response to climate change. In steady-state experiments: axenic T. pseudonana cells in four biological replicates (duplicate chemostats x 2 experimental runs) were acclimated to nitrate-limitation at 70% (1.5 day-1) of max growth rate for >10 days (>15 generations) under continuous light of 80 µmol photons·m?2·s?1. Cell biomass was maintained at ~2 x 105 cells·mL?1 by 10 ?M nitrate and carbonate chemistry stabilized to 300, 475 or 800 ?atm CO2, verified by pH and DIC measurements. Transition samples and carbonate chemistry were collected daily from chemostat cultures as CO2 levels were increased from ~300-800 ?atm at a rate ? 0.2 ?atm·min?1 over four consecutive days (6 generations) after pre-acclimation to 300 ?atm CO2 and nitrate-limitation.
2015-04-17 | E-GEOD-67971 | biostudies-arrayexpress
Project description:Regional brain glucose use was measured in rats with streptozotocin-induced diabetes (65 mg/kg intravenously) of 1 or 4 weeks duration, by using [6-14C]glucose and quantitative autoradiography. The concentrations of several metabolites were measured in plasma and brain. Results were compared with those from normal untreated rats. Glucose concentrations were increased in both plasma and brain, to similar degrees in both diabetic groups. Plasma ketone-body concentrations were 0.25, 1.0, and 3.15 mumol/ml in the control, 1-week and 4-week groups respectively (sum of acetoacetate and 3-hydroxybutyrate). Glucose use was increased throughout the brain (differences were statistically significant in 55 of 59 brain areas) after 1 week of diabetes, with an increase of 25% for the brain as a whole. In contrast, normal rates were found throughout the brain after 4 weeks of diabetes. None of the brain areas was affected significantly differently from the others, in either diabetic group. There was no significant loss of 14C as lactate or pyruvate during the experimental period, nor was there any indication of net production of lactate in any of the groups. Other methodological considerations that could have affected the results obtained in the diabetic rats were likewise ruled out. Because the ketone bodies are expected to supplement glucose as a metabolic fuel for the brain, our results indicate that brain energy consumption is increased during streptozotocin-diabetes.
| S-EPMC1148665 | biostudies-other