Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle
Previous ¹³C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2014-04, Vol.111 (14), p.5385-5390 |
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| creator | Patel, Anant B. Lai, James C. K. Chowdhury, Golam M. I. Hyder, Fahmeed Rothman, Douglas L. Shulman, Robert G. Behar, Kevin L. |
| description | Previous ¹³C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy- d -glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG ₆P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG ₆P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo , indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions. |
| doi_str_mv | 10.1073/pnas.1403576111 |
| format | Article |
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K. ; Chowdhury, Golam M. I. ; Hyder, Fahmeed ; Rothman, Douglas L. ; Shulman, Robert G. ; Behar, Kevin L.</creator><creatorcontrib>Patel, Anant B. ; Lai, James C. K. ; Chowdhury, Golam M. I. ; Hyder, Fahmeed ; Rothman, Douglas L. ; Shulman, Robert G. ; Behar, Kevin L.</creatorcontrib><description>Previous ¹³C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy- d -glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG ₆P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG ₆P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo , indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1403576111</identifier><identifier>PMID: 24706914</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Astrocytes ; Astrocytes - metabolism ; Biological Sciences ; Brain ; cortex ; Glucose ; Glucose - metabolism ; glutamic acid ; glutamine ; Glycolysis ; Lactates ; Lactic Acid - metabolism ; metabolites ; Modeling ; Molecules ; nerve tissue ; Nerves ; Neurons ; Neurons - metabolism ; Oxidation ; Phosphorylation ; prediction ; pyruvic acid ; Rats ; Rodents ; Seizures ; spectroscopy ; stable isotopes ; stoichiometry</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2014-04, Vol.111 (14), p.5385-5390</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Apr 8, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-bff945e77a4acce208196b9c6dd7ccd4993eb6fd8f23b843cfc59439107efbe43</citedby><cites>FETCH-LOGICAL-c557t-bff945e77a4acce208196b9c6dd7ccd4993eb6fd8f23b843cfc59439107efbe43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/111/14.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/23771419$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/23771419$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24706914$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Patel, Anant B.</creatorcontrib><creatorcontrib>Lai, James C. K.</creatorcontrib><creatorcontrib>Chowdhury, Golam M. I.</creatorcontrib><creatorcontrib>Hyder, Fahmeed</creatorcontrib><creatorcontrib>Rothman, Douglas L.</creatorcontrib><creatorcontrib>Shulman, Robert G.</creatorcontrib><creatorcontrib>Behar, Kevin L.</creatorcontrib><title>Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Previous ¹³C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy- d -glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG ₆P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG ₆P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo , indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions.</description><subject>Animals</subject><subject>Astrocytes</subject><subject>Astrocytes - metabolism</subject><subject>Biological Sciences</subject><subject>Brain</subject><subject>cortex</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>glutamic acid</subject><subject>glutamine</subject><subject>Glycolysis</subject><subject>Lactates</subject><subject>Lactic Acid - metabolism</subject><subject>metabolites</subject><subject>Modeling</subject><subject>Molecules</subject><subject>nerve tissue</subject><subject>Nerves</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Oxidation</subject><subject>Phosphorylation</subject><subject>prediction</subject><subject>pyruvic acid</subject><subject>Rats</subject><subject>Rodents</subject><subject>Seizures</subject><subject>spectroscopy</subject><subject>stable isotopes</subject><subject>stoichiometry</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkk2P0zAQhiMEYpeFMyfAEhcu2fXEdhxfkNDyKa3EAfZsOc6kdZXGwXaK-gv427jb0gKXPViWPM881ryaongO9BKoZFfTaOIlcMqErAHgQXEOVEFZc0UfFueUVrJseMXPiicxriilSjT0cXFWcUlrBfy8-PXeBbSJ4MZ1OFokvQ_E2OQ2Lm3LDicc83sii2G2PiKZlj7mE7aDSc6PxI1kxDn4MZKfLi2JW0-Ds3e1eOdKSyQmpuDtNmGZfLnHyZA_MQlJXM4pDfi0eNSbIeKzw31R3H788P36c3nz9dOX63c3pRVCprLte8UFSmm4sRYr2oCqW2XrrpPWdlwphm3dd01fsbbhzPZWKM5UDgv7Fjm7KN7uvdPcrrGzebZgBj0FtzZhq71x-t_K6JZ64TeaqaaGSmbBm4Mg-B8zxqTXLlocBjOin6OGhjJgvAJ2P1rLmgkFit-PCuCcMcEho6__Q1d-DmMObUc1kDORO-pqT9ngYwzYH0cEqnero3ero0-rkzte_p3Mkf-zKxl4dQB2nUcdQLZowRqRiRd7YhWTDycDkxI4qJOhN16bRXBR336rKNSU5vG4UOw3MEzgug</recordid><startdate>20140408</startdate><enddate>20140408</enddate><creator>Patel, Anant B.</creator><creator>Lai, James C. 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| subjects | Animals Astrocytes Astrocytes - metabolism Biological Sciences Brain cortex Glucose Glucose - metabolism glutamic acid glutamine Glycolysis Lactates Lactic Acid - metabolism metabolites Modeling Molecules nerve tissue Nerves Neurons Neurons - metabolism Oxidation Phosphorylation prediction pyruvic acid Rats Rodents Seizures spectroscopy stable isotopes stoichiometry |
| title | Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle |
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