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Exchange-mediated dilution of brain lactate specific activity: implications for the origin of glutamate dilution and the contributions of glutamine dilution and other pathways.

ABSTRACT: The magnitude of metabolic activation is greatly underestimated in autoradiographic studies using [1- or 6-14C]glucose compared to parallel assays with [14C]deoxyglucose indicating that most of the label corresponding to the additional [14C]glucose consumed during activation compared to rest is quickly released from activated structures. Label could be lost by net release of [14C]lactate from brain or via lactate exchange between blood and brain. These possibilities were distinguished by comparison of glucose and lactate specific activities in arterial blood and brain before, during, and after generalized sensory stimulation and during spreading cortical depression. Over a wide range of brain lactate concentrations, lactate specific activity was close to the theoretical maximum, i.e. half that of [6-14C]glucose, indicating that exchange-mediated dilution of lactate is negligible and that efflux of [14C]lactate probably accounts for most of the label loss. Low lactate dilution also indicates that dilution of glutamate C4 fractional enrichment in [13C]glucose studies, currently ascribed predominantly to lactate exchange, arises from other unidentified pathways or factors. Alternative explanations for glutamate dilution (presented in Supporting Information) include poorly labeled amino acid pools and oxidative metabolism of minor substrates in astrocytes to first dilute the astrocytic glutamine pool, followed by dilution of glutamate via glutamate-glutamine cycling.

SUBMITTER: Dienel GA

PROVIDER: S-EPMC2756232 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Exchange-mediated dilution of brain lactate specific activity: implications for the origin of glutamate dilution and the contributions of glutamine dilution and other pathways.

Dienel Gerald A GA Cruz Nancy F NF

Journal of neurochemistry 20090501

The magnitude of metabolic activation is greatly underestimated in autoradiographic studies using [1- or 6-14C]glucose compared to parallel assays with [14C]deoxyglucose indicating that most of the label corresponding to the additional [14C]glucose consumed during activation compared to rest is quickly released from activated structures. Label could be lost by net release of [14C]lactate from brain or via lactate exchange between blood and brain. These possibilities were distinguished by compari ...[more]

PMID: 19393006

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Project description:Energy metabolism in proliferating cultured rat thymocytes was compared with that of freshly prepared non-proliferating resting cells. Cultured rat thymocytes enter a proliferative cycle after stimulation by concanavalin A and Lymphocult T (interleukin-2), with maximal rates of DNA synthesis at 60 h. Compared with incubated resting thymocytes, glucose metabolism by incubated proliferating thymocytes was 53-fold increased; 90% of the amount of glucose utilized was converted into lactate, whereas resting cells metabolized only 56% to lactate. However, the latter oxidized 27% of glucose to CO2, as opposed to 1.1% by the proliferating cells. Activities of hexokinase, 6-phosphofructokinase, pyruvate kinase and aldolase in proliferating thymocytes were increased 12-, 17-, 30- and 24-fold respectively, whereas the rate of pyruvate oxidation was enhanced only 3-fold. The relatively low capacity of pyruvate degradation in proliferating thymocytes might be the reason for almost complete conversion of glucose into lactate by these cells. Glutamine utilization by rat thymocytes was 8-fold increased during proliferation. The major end products of glutamine metabolism are glutamate, aspartate, CO2 and ammonia. A complete recovery of glutamine carbon and nitrogen in the products was obtained. The amount of glutamate formed by phosphate-dependent glutaminase which entered the citric acid cycle was enhanced 5-fold in the proliferating cells: 76% was converted into 2-oxoglutarate by aspartate aminotransferase, present in high activity, and the remaining 24% by glutamate dehydrogenase. With resting cells the same percentages were obtained (75 and 25). Maximal activities of glutaminase, glutamate dehydrogenase and aspartate aminotransferase were increased 3-, 12- and 6-fold respectively in proliferating cells; 32% of the glutamate metabolized in the citric acid cycle was recovered in CO2 and 61% in aspartate. In resting cells this proportion was 41% and 59% and in mitogen-stimulated cells 39% and 65% respectively. Addition of glucose (4 mM) or malate (2 mM) strongly decreased the rates of glutamine utilization and glutamate conversion into 2-oxoglutarate by proliferating thymocytes and also affected the pathways of further glutamate metabolism. Addition of 2 mM-pyruvate did not alter the rate of glutamine utilization by proliferating thymocytes, but decreased the rate of metabolism beyond the stage of glutamate significantly. Formation of acetyl-CoA in the presence of pyruvate might explain the relatively enhanced oxidation of glutamate to CO2 (56%) by proliferating thymocytes.

Dataset Information

Exchange-mediated dilution of brain lactate specific activity: implications for the origin of glutamate dilution and the contributions of glutamine dilution and other pathways.

Publications

Exchange-mediated dilution of brain lactate specific activity: implications for the origin of glutamate dilution and the contributions of glutamine dilution and other pathways.

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