Abstract
Most glycogen in cerebral cortex is located in astrocytes, and the importance of glycogenolysis for critical functions, including neurotransmission and memory consolidation, is strongly supported by many studies. However, specific mechanisms through which glycogen sustains essential functions remain to be established by rigorous, quantitative studies. Cerebral cortical glycogen concentrations are in the range of 10–12 μmol/g in carefully-handled animals, and the calculated rate of glycogenolysis (CMRglycogen) during sensory stimulation is approximately 60% that of glucose utilization (CMRglc) by all cells, with lower rates during acute hypoglycemia and exercise to exhaustion. CMRglycogen is at least fourfold higher when the volume fraction of astrocytes is taken into account. Inclusion of glycogen consumed during sensory stimulation in calculation of the oxygen-glucose index (OGI = CMRO2/CMRglc, which has a theoretical maximum of 6 when no other substrates are metabolized) reduces OGI from 5.0 to 2.8. Thus, at least 53% of the carbohydrate is not oxidized, suggesting that glycogen mobilization supports astrocytic glycolysis, not neuronal oxidation of glycogen-derived lactate that would cause OGI to exceed 6. Failure of glycogenolysis to dilute the specific activity of lactate formed from blood-borne [6-14C]glucose indicates compartmentation of glycolytic metabolism of glucose and glycogen and the rapid release from cerebral cortex of glycogen-derived lactate. Together, these findings invalidate the conclusion by others that glycogen-derived lactate is a major fuel for neurons during neurotransmission, memory consolidation, and exercise to exhaustion. Alternative mechanisms, including glucose sparing for neurons, are presented as testable explanations for data interpreted as lactate shuttling.
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Abbreviations
- (A-V)substrate:
-
Arteriovenous difference across the brain for the identified substrate
- Asp:
-
Aspartate
- BAY U6751:
-
4-(2-Chlorophenyl)-l-ethyl-1,4-dihydro-6-methyl-2,3,5-pyridinetricarboxylic acid 5-isopropyl ester disodium salt hydrate
- CBF:
-
Cerebral blood flow rate
- CMR:
-
Cerebral metabolic rate for substrate of interest = CBF(A-V)substrate
- CMRglc:
-
Cerebral metabolic rate for glucose = CBF(A-V)glc
- CMRglycogen:
-
Cerebral metabolic rate for glycogen = Δ[glycogen]/time
- CMRO2:
-
Cerebral metabolic rate for oxygen CBF(A-V)O2
- CP-316,819:
-
[R-R∗,S∗]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-l-(phenylmethyl)propyl]-1H-indole-2-carboxamide
- DAB:
-
1,4-Dideoxy-1,4-imino-d-arabinitol
- DG:
-
2-deoxy-d-glucose
- DMSO:
-
Dimethyl sulfoxide
- FDG:
-
2-fluoro-2-deoxy-d-glucose
- Glc:
-
Glucose
- Glc-6-P:
-
Glucose-6-phosphate
- Gln:
-
Glutamine
- Glu:
-
Glutamate
- GLUT:
-
Glucose transporter; GLUT1 in vascular endothelium and astrocytes, and GLUT3 and GLUT4 in neurons
- GPR81:
-
G-protein-coupled lactate receptor81, also known as HCAR1
- HCAR1:
-
Hydroxycarboxylic acid receptor1 also known as GPR81
- KO:
-
Knockout
- Lac:
-
Lactate
- LTP:
-
Long-term potentiation
- MCT:
-
Monocarboxylic acid transporter; MCT1 and MCT4 isoforms are mainly astrocytic, whereas MCT2 is predominantly neuronal
- NMDA:
-
N-Methyl-d-aspartate
- OCI:
-
Oxygen carbohydrate index = CMRO2/[CMRglc + 0.5CMRlac + CMRglycogen] = (A-V)O2/((A-V)glc + 0.5(A-V)lac + Δ[glycogen]), where lactate and [glycogen] are expressed in glucosyl units (2Lac = 1Glc)
- OGI:
-
Oxygen-glucose index = CMRO2/CMRglc = (A-V)O2/(A-V)glc (CBF cancels out). This calculation assumes no other substrates are oxidized
- PAPs:
-
Peripheral astrocytic processes
- RSA:
-
Relative specific activity (SA) = ratio of the SA of a compound of interest to the SA of a reference compound, e.g., SA lactate/SA glucose
- SA:
-
Specific activity (dpm/μmol)
- TCA:
-
Tricarboxylic acid
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Dienel, G.A., Rothman, D.L. (2019). Glycogenolysis in Cerebral Cortex During Sensory Stimulation, Acute Hypoglycemia, and Exercise: Impact on Astrocytic Energetics, Aerobic Glycolysis, and Astrocyte-Neuron Interactions. In: DiNuzzo, M., Schousboe, A. (eds) Brain Glycogen Metabolism. Advances in Neurobiology, vol 23. Springer, Cham. https://doi.org/10.1007/978-3-030-27480-1_8
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