J Physiol (2003), 546.2, p. 325
035105
The Physiological Society 2002
How to balance the brain
energy budget while
Journal of Physiology
spending glucose differently
Luc Pellerin and Pierre J. Magistretti
Institut de Physiologie, Universit de
Lausanne, 1005 Lausanne, Switzerland
Email: Luc.Pellerin@iphysiol.unil.ch
or Pierre.Magistretti@iphysiol.unil.ch
The brain is an organ with high energy
demands. Thus, while it represents only 2 % of
the body weight, it contributes up to 20 % of its
resting metabolism. Glucose is considered the
almost exclusive blood-borne energy substrate
utilized by the adult brain to fuel its activity.
Most of the energy necessary for brain
function is derived from the full oxidation of
glucose. Recently, calculations of the energy
requirements for the different components
involved in brain activity have led to the
conclusion that the vast majority of energy
expenditure (81 %) is devoted to neuronal
excitatory signalling (Attwell & Laughlin,
2001). When estimations were made on a
cellular basis, it was concluded that no more
than 5 % of energy usage can be attributed to
glial function while the rest (comprising
resting consumption + signalling costs) is
accounted for by neurons. Although these
calculations do not allow any prediction
about the mechanims involved in energy
production, their distribution and proportion
among various cell types nor the possibility of
metabolite exchange, the aforementioned
conclusions about the prominent role of
Figure 1
A, classical brain energy budget; B, new brain
economy with lactate exchange.
DOI: 10.1113/jphysiol.2002.
PERSPECTIVES
glucose oxidation seriously restrict the
possibilities. As a logical consequence, one
would predict that the proportion of glucose
utilized by neurons should approach 95 %
while the remaining 5 % should be enough to
satisfy the modest glial energy needs (Fig. 1A).
In return, oxidation of 2 lactate by the neuron
In this issue of The Journal of Physiology, Vga
et al. (2003) studied the uptake and
distribution of locally applied deoxyglucose,
glucose or lactate in a rat vagus nerve
preparation. Using a particularly elegant
method to track the radioactively labelled
metabolites and to model their diffusion as
well as their distribution between two
compartments (axons and Schwann cells),
they come to the unexpected conclusion
that approximately 78 % of the labelled
2-deoxyglucose (and by extension of glucose
utilization) occurs in Schwann cells, the
counterparts of astrocytes in the peripheral
nervous system. How can this be possible
without violating the energy budget rules?
One rule-breaking possibility could be that
the energy-requiring processes and energy-
producing pathways used in the peripheral
nervous system are different from those in
the central nervous system. This does not
appear to be the case since it has long been
known that active transport of ions necessary
to re-establish the electrochemical gradients
dissipated by action potential propagation is
the predominant ATP-consuming process in
nerves, also accounting for almost all oxygen
consumption in this preparation (Ritchie,
1967).
A possible solution to this apparent paradox
is offered by previous work suggesting the
existence of a net lactate transfer from glial
cells to neurons, known as the lactate
shuttle hypothesis (Magistretti et al. 1999).
Thus, it was postulated that in the central
nervous system, astrocytes could respond to
increased synaptic activity via glutamate
uptake by increasing their rate of aerobic
glycolysis, i.e. glucose consumption and
lactate production (Pellerin & Magistretti
1994). After its release from astrocytes, lactate
would be taken up by neurons via a specific
monocarboxylate transporter and used as
energy substrate. Mounting evidence has
been provided indicating that lactate could
constitute a significant energy substrate for
neurons both in peripheral nerves and in the
brain. Moreover, the existence of a lactate
shuttle between cells within the same tissue is
not unique to the nervous system since it
has been already reported in other tissues
(e.g. striated muscle), suggesting that it might
be a rather universal concept (Brooks, 2002).
Data presented by Vga et al. (2003) strongly
indicate that a net transfer of energy substrate
must be taking place between Schwann cells
and axons, and points at lactate as the likely
candidate.
www.jphysiol.org
What is the consequence of this alternative
distribution of glucose utilization on the ratio
of ATP production between neurons and
glial cells? Glycolysis occurring in glial cells
would provide 2 ATP and lead to the
production of 2 lactate per glucose consumed.
(or nerve) could potentially provide up to 36
ATP. Interestingly enough, this distribution
of ATP production respects the previously
established energy budget with ~5 % of the
ATP being produced in the glial cell while the
rest would be generated from lactate in the
neuron (Fig. 1B). Of course, peripheral nerves
and Schwann cells may represent an extreme
case of metabolic compartmentation, like the
retina where glial cells are almost exclusively
glycolytic while neuronal cells are highly
oxidative and glucose is predominantly taken
up by glial cells while released lactate is used
by neurons (Poitry-Yamate et al. 1995). It is
likely, however, that even in the central
nervous system a certain degree of such
metabolic preference exists and that lactate
exchange occurs to maintain an appropriate
energy substrate supply to the energy-
demanding neuron (see the recent article by
Ainscow et al. 2002). Moreover, the proportion
of glycolytically consumed glucose by glial
cells and lactate produced for utilization by
neurons may well vary according to the level
of neuronal activity. A signal triggering such
a metabolic response between astrocytes
and neurons both in the central nervous
system and in the retina has been identified as
the excitatory neurotransmitter glutamate.
Whether a similar signal is sent from axons to
Schwann cells is not known although some
candidates such as K+ could be proposed. The
dogma that glucose is fully oxidized by the
brain is still valid. However, new data obtained
in experimental models affording a cellular
resolution strongly suggest a contribution
from glial cells via aerobic glycolysis that will
provide lactate to meet the energy demands
of nerve cells where the monocarboxylate
would be fully oxidized.
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