Sugar for the brain: the role of glucose in physiological and pathological brain function

doi:10.1016/j.tins.2013.07.001

Trends in Neurosciences

Volume 36, Issue 10, October 2013, Pages 587-597

https://doi.org/10.1016/j.tins.2013.07.001 Get rights and content

Highlights

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We provide a comprehensive overview of the role of glucose metabolism in normal brain function.
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We analyze the contribution of glucose metabolism to brain physiology.
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We discuss controversies in energy substrate consumption and utilization.
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We highlight the connection between glucose metabolism and cell death.
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We review the pathophysiological consequences of balanced and disturbed glucose metabolism.

The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We synthesize these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation that lead to disease.

Section snippets

Glucose metabolism: fueling the brain

The mammalian brain depends on glucose as its main source of energy. In the adult brain, neurons have the highest energy demand [1], requiring continuous delivery of glucose from blood. In humans, the brain accounts for approximately 2% of the body weight, but consumes approximately 20% of glucose-derived energy, making it the main consumer of glucose (approximately 5.6 mg glucose per 100 g human brain tissue per minute [2]). Glucose metabolism provides the fuel for physiological brain function

Glucose metabolism: the bioenergetic basis for neurotransmission

The largest proportion of energy in the brain is consumed for neuronal computation and information processing [3]; for example, the generation of action potentials and postsynaptic potentials generated after synaptic events (Figure 1D), and the maintenance of ion gradients and neuronal resting potential 1, 4. Additionally, glucose metabolism provides the energy and precursors for the biosynthesis of neurotransmitters (for a comprehensive overview, see [5]). Importantly, astrocytic glycogen

Glucose uptake in the brain: how are neurons and astrocytes fed?

Dependence of the brain on glucose as its obligatory fuel derives mainly from the blood–brain barrier (BBB; see Glossary), and its selective permeability for glucose in the adult brain. Glucose cannot be replaced as an energy source, but it can be supplemented, as during strenuous physical activity when blood lactate levels are elevated [14] or during prolonged starvation [15] when blood levels of ketone bodies are elevated and BBB monocarboxylic acid transporter (MCT) levels are upregulated.

Metabolic interactions among astrocytes and neurons, and lactate shuttling

Both neurons 16, 27, 28 and astrocytes 18, 29 have been described as the main consumers of glucose. The cellular contributions to overall glucose utilization has been a controversial issue for decades because current technology does not have adequate spatiotemporal resolution to quantify metabolic activity in single cells in vivo. Two conflicting concepts describe the predominant cellular fate of glucose during brain activation and propose different directions and magnitudes of shuttling of

Glucose metabolism and the regulation of CBF

Under resting conditions, local CBF is highest in brain regions with the highest local glucose metabolism. All brain regions are metabolically active at all times, but there is a large heterogeneity among various brain structures. During functional activation, the increase in local CBF usually parallels the increase in CMR_glc, whereas the increase in oxygen metabolism is lower [36]. However, there is at least one example where, under peripheral somatosensory stimulation, local CBF in the

Brain–body axis: central control over peripheral glucose metabolism

Given that the brain relies on exogenous nutrient supplies, it is not surprising that it can increase these supplies, especially glucose, by regulating systemic homeostasis and food intake 49, 50 (Figure 1A). Specialized neuronal networks in the hypothalamic arcuate nucleus and in the hindbrain sense, integrate, and regulate energy homeostasis and glucose levels, and signal to the periphery through a dedicated neuronal network 49, 50, 51. Indeed, central glucose sensing and peripheral

Glucose metabolism and the regulation of cell death

Glucose metabolism is evolutionarily linked to the regulation of cell death [71] (Figures 1E and 3A), and this link is tightly controlled in a similar fashion in many cell types, arguing for a universal role of coregulated metabolic and apoptotic pathways. Neurons and cancer cells are among the cell types that rely almost exclusively on glucose metabolism for energy generation, and recent evidence suggests that these cells use similar mechanisms to adapt to substrate deprivation and promote

Disease mechanisms

Neurons are largely intolerant of an inadequate energy supply and, thus, the high energy demand of the brain predisposes it to a variety of diseases if energy supplies are disrupted. Various CNS pathologies are the consequence, and sometimes also the cause, of disturbed central or peripheral glucose energy metabolism, which can be affected at almost every level of the cellular or biochemical metabolic cascades (Figure 1). Changes in the glucose metabolism of affected patients can efficiently be

Concluding remarks

Glucose metabolism is closely integrated with brain physiology and function. Although recent studies have shed light on the complex regulation of biochemical, cellular, and systemic pathways, many features of the exact regulation remain controversial or elusive (Box 3). The advent of novel and refined biochemical or genetic tools, screening methods, imaging technologies, and systems analyses will enable the study of cellular, subcellular, and even biochemical mechanisms in the cell or in vivo

Acknowledgments

We are grateful to the members of our labs for their contribution to our underlying research. We would like to thank Ralph Buchert, Department of Nuclear Medicine, Charité, for kindly providing and analyzing the PET images. This work was supported by the Seventh Framework Programme of the European Union (FP7/2008-2013) under Grant Agreements 201024 and 202213 (European Stroke Network), the Deutsche Forschungsgemeinschaft (NeuroCure Cluster of Excellence, Exc 257; SyNergy, Munich Cluster for

Glossary

Autophagy: an intracellular ‘recycling’ pathway that can be activated under conditions of metabolic stress to inhibit cell death. It involves the lysosomal degradation of cytoplasmic proteins or entire organelles for catabolic regeneration of nutrient pools [61].
Blood–brain barrier (BBB): the permeability barrier arising from tight junctions between brain endothelial cells, restricting diffusion from blood to brain. Entry into the brain is limited to molecules that can diffuse across membranes

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Trends in Neurosciences

ReviewSugar for the brain: the role of glucose in physiological and pathological brain function

Highlights

Section snippets

Glucose metabolism: fueling the brain

Glucose metabolism: the bioenergetic basis for neurotransmission

Glucose uptake in the brain: how are neurons and astrocytes fed?

Metabolic interactions among astrocytes and neurons, and lactate shuttling

Glucose metabolism and the regulation of CBF

Brain–body axis: central control over peripheral glucose metabolism

Glucose metabolism and the regulation of cell death

Disease mechanisms

Concluding remarks

Acknowledgments

Glossary

Neuron

Cell Calcium

Cell

Trends Neurosci.

J. Biol. Chem.

Neuroscience

Neuroimage

Neurochem. Int.

Neurochem. Int.

Brain Res.

Cell Metab.

Cell Metab.

Cell Metab.

Cell Metab.

Mol. Cell

Cell Metab.

Cell Metab.

Cell

Curr. Opin. Cell Biol.

Mol. Cell

J. Biol. Chem.

Cell

Lancet Neurol.

Neuron

Trends Neurosci.

Trends Neurosci.

Lancet Neurol.

Lancet Neurol.

Updated energy budgets for neural computation in the neocortex and cerebellum

J. Cereb. Blood Flow Metab.

[The glucose consumption of the brain & its dependence on the liver]

Arch. Psychiatr. Nervenkr. Z. Gesamte Neurol. Psychiatr.

Fueling and imaging brain activation

ASN Neuro

What learning in day-old chickens can teach a neurochemist: focus on astrocyte metabolism

J. Neurochem.

Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism

Cereb. Cortex

Is lactate a volume transmitter of metabolic states of the brain?

Front. Neuroenerget.

Energy-efficient action potentials in hippocampal mossy fibers

Science

Energy demand of synaptic transmission at the hippocampal Schaffer-collateral synapse

J. Cereb. Blood Flow Metab.

The energetics of CNS white matter

J. Neurosci.

Energetics of functional activation in neural tissues

Neurochem. Res.

Blood lactate is an important energy source for the human brain

J. Cereb. Blood Flow Metab.

Supply and demand in cerebral energy metabolism: the role of nutrient transporters

J. Cereb. Blood Flow Metab.

Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons

J. Neurochem.

Astroglial metabolic networks sustain hippocampal synaptic transmission

Science

Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function

J. Exp. Biol.

Glucose consumption in the cerebral cortex of rat during bicuculline-induced status epilipticus

J. Neurochem.

Brain lactate metabolism: the discoveries and the controversies

J. Cereb. Blood Flow Metab.

A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: implications for glycogen turnover

J. Neurochem.

The role of astrocytic glycogen in supporting the energetics of neuronal activity

Review
Sugar for the brain: the role of glucose in physiological and pathological brain function