BRAIN GLUCOSE METABOLISM: INTEGRATION OF ENERGETICS WITH FUNCTION

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I. Introduction

A. Glucose: The Brain's Obligatory Fuel

• Earliest studies in 1920s-1930s showed carbohydrate as major fuel

• Respiratory quotient (RQ) of 1.00 indicates carbohydrate metabolism

• Glucose established as major energy source for brain

• Most glucose oxidized to CO2 + H2O, some converted to lactate

B. Minor Oxidative Substrates

• Short-chain monocarboxylic acids, octanoate, decanoate

• Fatty acids readily oxidized by astrocytes

• Amino acids can be oxidized but contribute less than glucose

C. Glucose-Derived ATP and Carbon

• Brain relies on glucose catabolism for ATP generation

• Glucose is precursor for many compounds synthesized in brain

• ~70% of energy demands associated with neuronal signaling

• ~30% for nonsignaling activities

D. Assay Methods

• Radioactive and stable isotopes used to track metabolism

• Development of [14C]DG and [18F]FDG methods for imaging

• Magnetic resonance spectroscopy (MRS) for metabolic studies

E. Metabolic Rates

• Whole-brain CMRglc in humans ~0.2-0.3 μmol/g/min

• Brain consumes ~91g glucose/day

• Whole-brain CMRO2 ~3.3-4.2 ml/100g/min or 1.5-1.9 μmol/g/min

F. High Oxidative Rate

• Brain recognized as highly oxidative organ

• Can increase CMRO2 by 2-3 fold for at least 2 hours

• Higher metabolic rate during development

G. Consequences of Insufficient Glucose or Oxygen

• Hypoglycemia or hypoxia can degrade brain function

• Severity depends on magnitude and duration of deficit

• Even with acclimatization, cognitive deficits can occur at high altitudes

H. Perspective

• Glucose fulfills many essential functions in brain

• Quantitative assays of glucose utilization and pathway fluxes

• Complexities of glucose involvement in neurotransmission

• Controversial topics: astrocyte-neuron lactate shuttling, aerobic glycolysis, glycogen roles

II. Glucose Metabolism and Metabolic Assays

A. Major Pathways of Glucose Metabolism in Brain

1. Glucose delivery to brain

• Transported via GLUT transporters

• Brain-to-plasma distribution ratio ~0.2

• Maximal transport capacity 2-3 fold greater than resting utilization

2. ATP generation from glucose catabolism

• Glycolysis produces 2 ATP

• Oxidation produces ~30 ATP

• Total yield ~32 ATP per glucose molecule oxidized

doi:10.1152/physrev.00062.2017

Glucose is the long-established, obligatory fuel for brain that fulfills many critical functions, including ATP production, oxidative stress management, and synthesis of neurotransmitters, neuromodulators, and structural components. Neuronal glucose oxidation exceeds that in astrocytes, but both rates increase in direct proportion to excitatory neurotransmission; signaling and metabolism are closely coupled at the local level. Exact details of neuron–astrocyte glutamate– glutamine cycling remain to be established, and the specific roles of glucose and lactate in the cellular energetics of these processes are debated. Glycolysis is preferentially upregulated during brain activation even though oxygen availability is sufficient (aerobic glycolysis). Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in excess of oxygen, and adrenergic regulation of aerobic glycolysis draws attention to astrocytic metabolism, particularly glycogen turnover, which has a high impact on the oxygen– carbohydrate mismatch. Aerobic glycolysis is proposed to be predominant in young children and specific brain regions, but re-evaluation of data is necessary. Shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation, neurotransmission, and memory consolidation are controversial topics for which alternative mechanisms are proposed. Nutritional therapy and vagus nerve stimulation are translational bridges from metabolism to clinical treatment of diverse brain disorders