Lactate Utilization by Brain Cells and its
Role in CNS Development
Jose´ M. Medina
and Arantxa Tabernero
Department of Biochemistry and Molecular Biology, INCYL, University of Salamanca, Spain
We studied the role played by lactate as an important
substrate for the brain during the perinatal period. Under
these circumstances, lactate is the main substrate for
brain development and is used as a source of energy and
carbon skeletons. In fact, lactate is used actively by brain
cells in culture. Neurons, astrocytes, and oligodendro-
cytes use lactate as a preferential substrate for both
energy purposes and as precursor of lipids. Astrocytes
use lactate and other metabolic substrates for the
synthesis of oleic acid, a new neurotrophic factor. Oligo-
dendrocytes mainly use lactate as precursor of lipids,
presumably those used to synthesize myelin. Neurons
use lactate as a source of energy and as precursor of
lipids. During the perinatal period, neurons may use
blood lactate directly to meet the need for the energy and
carbon skeletons required for proliferation and differen-
tiation. During adult life, however, the lactate used by
neurons may come from astrocytes, in which lactate is
the ﬁnal product of glycogen breakdown. It may be con-
cluded that lactate plays an important role in brain
development. © 2004 Wiley-Liss, Inc.
Key words: lactic acid; neurons; astrocytes; oligoden-
drocytes; oleic acid
Although the metabolism of lactate by the brain is
now a hot issue (Pellerin, 2003; Gladden, 2004), early
work showed evidence supporting the crucial role played
by lactate in brain metabolism. In fact, lactate is used by
the brain in fetal (Bolan˜os and Medina, 1993), early new-
born (Arizmendi and Medina, 1983; Ferna´ndez and
Medina, 1986; Vicario et al., 1991; Vicario and Medina,
1992), and suckling rats (Itoh and Quastel, 1970; Dom-
browski et al., 1989), in adult rat hippocampus (Schurr et
al., 1988), in newborn dogs (Hellmann et al., 1982), and
in glucose-6-phosphatase-deﬁcient human infants (Fer-
nandes et al., 1984). Lactate utilization by the brain during
postnatal period is particularly relevant because in some
species such as human, brain develops during this period.
This requires a continuous supply of metabolic substrates
around birth to maintain brain development. Striking
changes in the fuel supply to the tissues occur during the
perinatal period because the transplacental supply of nu-
trients ends with a period of postnatal starvation (presuck-
ling period) followed by adaptation to a fat-rich diet. The
aim of the present work is to stress the role played by
lactate as a metabolic substrate for the brain during devel-
ENERGY HOMEOSTASIS OF THE BRAIN
DURING THE PERINATAL PERIOD
The supply of fuels to fetal tissues during gestation is
accomplished by transplacental passage of nutrients from
the mother, which are mostly glucose, amino acids, and
fatty acids. This placental mechanism of transport provides
fetal tissues with all the necessary fuels and cofactors to
support fetal development. In addition to glucose and
amino acids, fetal tissues can be also supplied with lactate,
which is an important substrate for the fetal brain during
late gestation (Shambaugh et al., 1977). Lactate is trans-
ported from the mother to the fetus through placental
membranes. In fact, the carrier-mediated transport of lac-
tate occurs in both maternal-sided (Balkovetz et al., 1988;
Alonso de la Torre et al., 1991a) and fetal-sided (Alonso de
la Torre et al., 1991b) syncytiotrophoblast membranes.
The main source of fetal lactate is the placenta itself,
however, because the synthesis of lactate from glucose is
very high in this tissue during late gestation. Alternatively,
fetal tissues may also synthesize lactate owing to the high
activity of anaerobic glycolysis in the fetus (Burd et al.,
1975; Battaglia, 1989). As a result, lactate accumulates in
fetal blood during late gestation (Girard et al., 1977).
Brain development cannot be interrupted despite its
restricted fuel supply. Indeed, maternal starvation in the rat
decreases the rate of lipogenesis in maternal and fetal
Contract grant sponsor: CICYT; Contract grant sponsor: MEC; Contract
grant sponsor: MCYT; Contract grant sponsor: FISSS; Contract grant
sponsor: Fundacio´n Ramo´n Areces, Spain.
*Corresponding author: Jose M. Medina, Departamento de Bioquı´mica y
Biologı´a Molecular, Universidad de Salamanca, Plaza de los Doctores de la
Reina s/n, 37007 Salamanca, Spain. E-mail: email@example.com
Received 19 July 2004; Revised 7 September 2004; Revised 9 September
Published online 30 November 2004 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/jnr.20336
Journal of Neuroscience Research 79:2–10 (2005)
© 2004 Wiley-Liss, Inc.
tissues except fetal brain, in which the rate of lipid syn-
thesis remains unchanged (Lorenzo et al., 1982). Maternal
starvation increases ketone body concentrations in fetal
and maternal blood (Girard et al., 1977), suggesting that in
these circumstances ketone bodies may replace glucose as
the main metabolic substrate (Shambaugh et al., 1977). In
agreement with this suggestion, maternal starvation in-
creases the activity of the monocarboxylate transporter of
placental syncytiotrophoblast membrane that is responsible
for the transport of lactate and ketone bodies (Alonso de la
Torre et al., 1992). This may be a mechanism to preserve
brain development under circumstances in which the glu-
cose supply is diminished. In this context, monocarboxy-
late transporters are present in fetal brain at midgestation
and their expression sharply increases during late fetal and
neonatal period (Baud et al., 2003; Fayol et al., 2004),
suggesting that the perinatal brain is able to take up lactate
efﬁciently. This is in agreement with early observation that
lactate transport to the brain in vivo is very active during
the perinatal period (Cremer, 1982).
Immediately after birth, the levels of insulin decrease,
coinciding with an abrupt increase in glucagon concen-
trations (Bla´zquez et al., 1974; Martı´n et al., 1981; Mayor
and Cuezva, 1985; Girard, 1990). The fall in the insulin/
glucagon ratio elicits glycogenolysis and gluconeogenesis
in the liver through the enhancement of cAMP concen-
trations. The surge of cAMP concentrations that follows
the decrease in the insulin/glucagon ratio is responsible for
the increase in the activities of liver glycogen phosphory-
lase and phosphoenolpyruvate carboxykinase (Mayor and
Cuezva, 1985). Consequently, hormonal changes occur-
ring around birth are responsible for the induction of
metabolic processes necessary for the newborn to adapt to
the new nutritional state in which glucose is scarce. De-
spite this, the newborn undergoes profound hypoglycemia
during the immediate postnatal period (Shelley and Neli-
gan, 1966; Exton, 1972; Martı´n et al., 1981; Mayor and
Cuezva, 1985; Girard, 1990). Both human and rat new-
borns show very low blood glucose concentrations
throughout the ﬁrst day of extrauterine life (Persson and
Tunell, 1971; Juanes et al., 1986). In the rat, there is a
tendency after 2 hr to regain normoglycemia, probably
due to the stimulation of liver glycogenolysis and the
progressive induction of gluconeogenesis (Mayor and
Cuezva, 1985; Girard, 1990). This hypoglycemic period is
longer in humans, probably because of the delay in glu-
coneogenesis induction observed in this species (Bougne-
res, 1987). It is surprising that the delay in glycogenolysis
onset apparently enhances vulnerability of the newborn.
Lactate availability during this period may supply energy
to neonatal tissues, however, reserving glucose for speciﬁc
Ketone bodies are a major fuel for the brain during
the suckling period and hence the stimulation of keto-
genesis at birth is an important metabolic event in
adaptation of the newborn to extrauterine life. Keto-
genesis is active during late gestation in human fetal
liver and the activity of ketogenic enzymes sharply
increases immediately after birth in the rat (Hahn and
Novak, 1985; Bougneres et al., 1986). In addition to
modulation of enzyme activities, the control of keto-
genesis also depends on the availability of fatty acids.
The increase in fatty acid concentrations that occurs
after delivery is due to breakdown of triacylglycerol in
white adipose tissue present in human newborns at
birth. In the rat, however, plasma fatty acids mostly
come from hydrolysis of triacylglycerols from the moth-
er’s milk because of the lack of white adipose tissue at
birth. Nevertheless, in both species, once lactation is
active fatty acids come from the intestinal hydrolysis of
milk triacylglycerols, which may be absorbed directly
without passage through the lymph (Aw and Grigor,
The increase in the activities of ketogenic enzymes
together with the increase in the availability of fatty acids
occurring immediately after delivery result in enhance-
ment of ketogenic capacity of the liver (Girard,1990). This
is responsible for the increase in ketone body concentra-
tions observed postnatally. In fact, plasma ketone body
concentrations are the main factor controlling the rate of
ketone body utilization by neonatal tissues (Robinson and
Williamson, 1980). In addition, activities of enzymes in-
volved in ketone body utilization either increase during
the ﬁrst days of extrauterine life, as in the rat (Page et al.,
1971), or are already induced during early gestation, as in
the human brain (Patel et al., 1975). Moreover, newborn
rat brain contains acetoacetyl-CoA synthetase, a unique
enzyme that allows an important portion of carbon atoms
from ketone bodies to be incorporated into lipid via a
highly efﬁcient cytosolic pathway (Williamson and Buck-
ley, 1973). Indeed, there is a strong correlation between
lipid synthesis and the activity of this enzyme during brain
development (Yeh and Sheehan, 1985). Moreover, ketone
body transport across the blood– brain barrier using the
monocarboxylate carrier is maximal during the suckling
period, in keeping with the idea that ketone bodies play an
important role in brain development (Cremer, 1982;
Conn et al., 1983).
Ketone bodies are utilized by the newborn brain as a
source of energy and carbon skeletons and are incorpo-
rated into fatty acids, sterols, acetylcholine, and amino
acids (Robinson and Williamson, 1980; Bougneres et al.,
1986). Ketone bodies, however, seem to be the major
source of carbon skeletons for sterol synthesis during brain
development and play a decisive role in the synthesis of
brain structures during myelinogenesis (Robinson and
Williamson, 1980; Miziorko et al., 1990). Ketone bodies
are utilized evenly by neurons, astrocytes, and oligoden-
drocytes (Edmond et al., 1987; Lopes-Cardozo et al.,
1989; Poduslo and Miller, 1991), indicating that they are
ubiquitous substrates for brain cells. Acetoacetyl-CoA syn-
thetase activity, however, is higher in oligodendrocytes
than in neurons or astrocytes, conﬁrming the special role
of oligodendrocytes in myelinogenesis (Pleasure et al.,
1979; Lopes-Cardozo et al., 1989; Poduslo and Miller,
Lactate Utilization by Brain Cells 3
LACTATE AS METABOLIC SUBSTRATE
FOR BRAIN DEVELOPMENT
Although the supply of metabolic substrates is main-
tained mostly during the perinatal period, there is an
apparent lack of mobilization of energy reserves immedi-
ately after delivery; i.e., during the presuckling period.
During this period, the maternal supply of glucose has
ceased and alternative substrates have not yet been re-
leased. In the rat, fatty acids come exclusively from the
mother’s milk because of the lack of white adipose tissue
at birth. Consequently, free fatty acids are not available in
the rat before the onset of suckling (Mayor and Cuezva,
1985; Girard, 1990). In the case of human newborns,
however, fatty acid mobilization occurs immediately after
birth, although the onset of ketogenesis is delayed, prob-
ably as a consequence of a limited supply of carnitine,
which is provided mainly by the milk (Hahn and Novak,
1985; Schmidt-Sommerfeld and Penn, 1990). In addition,
glycogenolysis and gluconeogenesis are not active imme-
diately after birth, resulting in very low concentrations of
plasma glucose (Mayor and Cuezva, 1985; Girard, 1990).
In these circumstances, lactate may play an important role
as an alternative substrate. In fact, lactate accumulates in
fetal blood during the perinatal period and is removed
rapidly immediately after delivery (Persson and Tunell,
1971; Juanes et al., 1986).
During the transition to extrauterine life, fetal
mitochondria undergo striking changes to enable them to
fulﬁll the functional requirements of an oxygen-rich en-
vironment. Rat liver mitochondria thus increase their
respiratory efﬁciency within the ﬁrst hours after delivery,
achieving full ability to use oxygen as a terminal acceptor
of electrons. This increases the efﬁciency of their meta-
bolic machinery to produce energy. The signal triggering
the enhancement of mitochondrial respiratory efﬁciency
may be the increase in oxygen availability because adenine
nucleotide accumulation by mitochondria apparently plays
an important role in the postnatal mitochondria setup
(Pollak, 1975; Aprille and Asimakis, 1980; Cuezva et al.,
1990). The increase in the synthesis of respiratory com-
plexes, however, together with the enhancement of F1-
ATPase synthesis may be the ﬁnal event responsible for the
postnatal increase in rat liver mitochondrial efﬁciency
(Valcarce et al., 1988; Cuezva et al., 1990). Consequently,
the increase in oxygen availability due to the onset of
ventilation is followed by striking changes in mitochon-
drial function, which increases the metabolic efﬁciency.
Oxygen concentrations are very low in the fetus although
the rate of oxidative metabolism in fetal tissues is detect-
able, suggesting that oxygen is exchanged rapidly between
maternal and fetal blood. Despite this, the rate of oxygen
utilization by the fetus is moderate compared to that of the
newborn during early neonatal life (Battaglia and Meschia,
1978; Girard and Ferre´ 1982). Blood oxygen concentra-
tions thus rise sharply immediately after delivery (Harris et
al., 1986; Juanes et al., 1986), concurrent with the en-
hancement of lactate and amino acid oxidation (Medina et
al., 1990; Vicario et al., 1990). Moreover, the increase in
oxygen availability may trigger the utilization of lactate
(Medina et al., 1990), thereby initiating postnatal energy
Actually, lactate accumulated during late gestation is
mostly removed within the ﬁrst hours of extrauterine life
(Persson and Tunell, 1971; Medina et al., 1990), indicating
that neonatal tissues actively utilize blood lactate. Because
gluconeogenesis is not yet induced in these circumstances
(Medina et al., 1980; Ferna´ndez et al., 1983), lactate is
utilized directly as a source of energy and carbon skeletons
for neonatal tissues (Medina et al., 1990). Lactate metab-
olism is particularly relevant in the brain, in which lactate
is preferred over glucose, glutamine, or ketone bodies
(Arizmendi and Medina, 1983; Ferna´ndez and Medina,
1986; Vicario et al., 1991). In addition, lactate is utilized
by the neonatal brain not only as a source of energy but
also as an excellent precursor of sterols and phospholipids
(Vicario and Medina, 1992). Consequently, lactate is the
main metabolic substrate for the brain during the presuck-
ling period. This provides a continuous supply of meta-
bolic fuels between delivery and the onset of suckling. It
should be mentioned that lactate transport across the
blood– brain barrier is maximal in the immature brain as
compared to that of adults (Cremer, 1982; Conn et al.,
1983; Pellerin et al., 1998a; Fayol et al., 2004). In addition,
hypoglycemia increases the rate of entry of lactate into the
brain, supporting the importance of lactate as a cerebral
substrate during the postnatal period (Hellmann et al.,
1982; Medina et al., 1990). Lactate inhibits glucose utili-
zation (Ferna´ndez and Medina, 1986; Vicario and Medina,
1992), suggesting that during the presuckling period it is
utilized as the main fuel, reserving glucose for speciﬁc
destinations such as oxidation by the pentose phosphate
pathway or glycerogenesis. Lactate utilization, however, is
presumably not inhibited by ketone bodies because the
presence of 3-hydroxybutyrate at physiologic concentra-
tions does not affect lactate metabolism (Vicario and
Medina, 1992). Once the onset of suckling takes place,
however, ketone bodies become the major fuel for brain
development. Under these circumstances, lactate would
be used as the major gluconeogenic substrate (Ferna´ndez
and Medina, 1986; Medina et al., 1990).
LACTATE UTILIZATION BY NEURONS
Because neonatal brain actively uses lactate, we de-
cided to investigate lactate metabolism in cultured brain
cells. When the rates of lactate utilization were measured
in neurons and astrocytes from primary culture under
optimal conditions and compared to those of other im-
portant metabolic substrates for the neonatal brain (Vicario
et al., 1993), it was observed that in both neurons and
astrocytes the rate of lactate utilization was higher than that
of glucose, 3-hydroxybutyrate, or glutamine. Lactate uti-
lization by neurons and astrocytes has been conﬁrmed
widely later by nuclear magnetic resonance (NMR) spec-
troscopy (Alves et al., 1995; Waagepetersen et al., 1998;
Qu et al., 2000; Bouzier-Sore et al., 2003; Tyson et al.,
2003). Despite the high rate of lactate utilization shown by
4 Medina and Tabernero
astrocytes in vitro (Vicario et al., 1993), later ﬁndings
(Bouzier-Sore et al., 2003; Itoh et al., 2003) suggest that in
physiologic circumstances neurons preferentially use lac-
tate rather than glucose to support oxidative metabolism
whereas astrocytes use glycolysis to supply neurons with
It is noteworthy that lactate was utilized by both
neurons and astrocytes not only as a source of energy but
also as a precursor of lipids (Vicario et al., 1993). Lactate
was thus incorporated preferentially into saponiﬁable frac-
tions in astrocytes (Tabernero et al., 1993), but sterol
synthesis was also relevant in neurons. In both types of
cells, the main phospholipid synthesized from lactate was
phosphatidylcholine and the main sterols synthesized were
lanosterol in neurons and desmosterol in astrocytes (Tab-
ernero et al., 1993). This is in agreement with the lipid
composition of the neonatal brain and conﬁrms the phys-
iologic role played by lactate in brain development.
LACTATE AS AN EXCHANGE SUBSTRATE
BETWEEN ASTROCYTES AND NEURONS
Although glucose-6-phosphatase activity has been
detected in some astrocytes (Bell et al., 1993), it is accepted
commonly that the activity of glucose-6-phosphatase is
negligible in astrocytes (Gotoh et al., 2000). This enzyme
catalyzes the last step in the pathway of glycogen break-
down and hence glucose-6-phosphate, not glucose, is the
end product of glycogenolysis in astrocytes. Accordingly,
the products of glycogen breakdown cannot leave the
astrocyte because the plasma membrane is not permeable
to phosphorylated compounds. This system may serve to
conﬁne glucose in the astrocyte end feet surrounding
capillaries, preventing its return to the blood. Glucose-6-
phosphate may cross gap junctions, however, reaching
adjacent astrocytes when it would be transformed into
lactate by glycolysis. Nevertheless, in the absence of gly-
cogenolysis, astrocytes in culture directly synthesize lactate
from extracellular glucose (Walz and Mukerji, 1998a,b)
suggesting that astrocytes may convert blood glucose into
lactate through glycolysis. Moreover, this process seems to
be regulated by synaptic activity, a fact consistent with the
idea that astrocytes modulate glycolytic activity in syn-
chrony with neuronal requirements of lactate (Bouzier-
Sore et al., 2002).
Lactate synthesized by astrocytes can freely cross the
plasma membrane and thus become available to neurons
(Pellerin et al., 1998b). It has been shown that the trans-
port of lactate into neurons is mediated by a speciﬁc carrier
(Dringen et al., 1993; Tildon et al., 1993; MacKenna et
al., 1998; Debernardi et al., 2003) and that these cells
exhibit a high capacity for lactate utilization (Tabernero et
al., 1993; Vicario et al., 1993). Lactate is also exported to
the extracellular medium by astrocytes in the form of
citrate or other tricarboxylic acid cycle (TCA) intermedi-
ates (Sonnewald et al., 1991; Westergaard et al., 1994;
Giaume et al., 1997). Consequently, neurons show a high
capacity for plasma lactate utilization because they are able
to use lactate released by astrocytes (Fig. 1). This may
explain why lactate is able to support neuronal activity
(Bock et al., 1993; Izumi et al., 1994; Maran et al., 1994).
In addition, during the postnatal period glucose availability
is scarce but much lactate is supplied from the blood.
Under these circumstances, lactate is therefore used by
both neurons and astrocytes to sustain brain development.
In this situation, however, glucose remains required by the
brain for the generation of NADPH and glycerol-borne
phospholipids. In agreement with this, when lactate is
available widely both neurons and astrocytes use glucose
for the synthesis of NADPH and ribose-5-phosphate in
the pentose-phosphate shunt or the synthesis of glycerol-
borne phospholipids (Tabernero et al., 1996b). Likewise,
the ability of neurons and astrocytes to metabolize lactate,
saving glucose for exclusive purposes, would explain why
lactate is able to support cerebral function during episodes
of hypoglycemia (Schurr et al., 1988; Bock et al., 1993;
Izumi et al., 1994; Maran et al., 1994). Under conditions
of hypoglycemia, lactate is thus presumably used to sustain
the bulk of cellular energy and carbon expenditure
whereas the scarce glucose available would be used for the
exclusive purposes that cannot be fulﬁlled by lactate.
LACTATE PASSAGE THROUGH
Gap junctions allow direct intercellular communica-
tion between the cytoplasm of neighboring cells. The
ultrastructure of a junctional channel is now well estab-
lished (Bennett et al., 1991), with each channel comprising
a ring of six protein subunits called connexins (Peracchia et
al., 1994; Bruzzone et al., 1996). The diffusion through
Fig. 1. Lactate metabolism in the brain. During the adult life, lactate is
used as an exchangeable substrate among brain cells to maintain energy
homeostasis in the CNS, supplying energy and carbon skeletons to
neurons or oligodendrocytes. Because astrocytes lack glucose-6-
phosphatase, glucose-6-phosphate would be transported to the adjacent
astrocytes through gap junctions (GJ) or converted in lactate through
glycolysis. During the perinatal period, lactate accumulated in fetal
blood is metabolized rapidly immediately after delivery, presumably to
meet the need for the energy and carbons skeletons required for
proliferation and differentiation of brain cells.
Lactate Utilization by Brain Cells 5
gap junctions of various energetic metabolites was evalu-
ated by adapting the scrape-loading dye transfer technique
(El-Fouly et al., 1987), using radioactive compounds and
following their intercellular spread by autoradiography
(Tabernero et al., 1996a). This technique was used to
demonstrate that astrocytic gap junctions are freely per-
meable to glucose, glucose-6-phosphate (Fig. 1), glu-
tamine, and glutamate (Tabernero et al., 1996a; Giaume et
al., 1997). Astrocytic gap junctions are also permeable to
lactate (Fig. 1), which may contribute to its diffusion
through brain structures (Tabernero et al., 1996a). There
is evidence suggesting that the passage of metabolites
through astrocytic gap junctions can be ﬁnely regulated. In
this context, we have shown (Granda et al., 1998) that gap
junction permeability is controlled by the activity of the
K-ATP channel. The K-ATP channel is composed of two
subunits, the inwardly rectifying K
channel (KIR) and
the sulfonylurea receptor (SUR) (Nicolino, 1997), the
latter conferring the channel sensitivity to ATP and sul-
fonylureas. The existence of the K-ATP channel has been
reported in the central nervous system (CNS) (Amoroso et
al., 1990) and is sensitive to sulfonylureas (Niki and Ash-
croft, 1993; Xia et al., 1993). Because sulfonylureas mimic
the effects of ATP on the K-ATP channel, it may be
proposed that intracellular ATP concentrations might reg-
ulate gap junction permeability (Vera et al., 1996) con-
trolling the K-ATP channel. The energy status of the
astrocyte would therefore be able to regulate intercellular
communication through gap junctions. When the energy
status of the astrocyte is sufﬁcient to sustain its own met-
abolic machinery, gap junction permeability would in-
crease to allow the passage of metabolites (Tabernero et al.,
1996a; Giaume et al., 1997) to adjacent cells. If the energy
reserves of the astrocyte were compromised, however,
ATP concentrations would decrease, resulting in a drop in
gap junction permeability (Vera et al., 1996). Conse-
quently, we have suggested that astrocytic gap junctions
play an important role in “pipelining” metabolic substrates
through the CNS by acting like waterway locks that allow
the establishment of a cell-to-cell metabolite gradient that
fuels the transport of substrates to targeted neurons (Tab-
ernero et al., 1996a; Giaume et al., 1997). Accordingly,
ATP concentrations may regulate the open/closed state of
the “locks” by controlling the activity of the K-ATP
channel. Once the incoming substrates have fulﬁlled the
energy requirements of the cells, gap junction permeability
would increase to allow spared metabolic substrates to pass
to adjacent cells, thus distributing energy and carbon skel-
etons through the CNS. If so, the K-ATP channel may
play an important role in controlling the transport of ions,
metabolites, and signals through the CNS, thus regulating
the crucial collaboration between astrocytes and neurons.
LACTATE AS A SOURCE OF OLEIC ACID,
A NEW NEUROTROPHIC FACTOR
The metabolic fate of lactate may be regulated by the
presence of albumin in the blood because the presence of
this protein in incubation medium increases the rate of
lactate incorporation into lipids by isolated cells from early
neonatal rat brain (Vicario et al., 1991). Moreover, in
cultured astrocytes albumin strongly increases (by more
than 100%) the ﬂux of substrates through the pyruvate
dehydrogenase (PDH)-catalyzed reaction (Tabernero et
al., 1999). This effect is dose dependent and speciﬁc to
albumin and is not mimicked by other proteins such as
␥-globulin or compounds of similar molecular weight
such as dextran. On the other hand, albumin only slightly
stimulates other metabolic pathways such as the TCA
cycle or the pentose phosphate pathway, indicating that
the effect of albumin is speciﬁc and exerted on the reaction
catalyzed by PDH. The presence of fatty acids, however,
counteracts the effect of albumin, suggesting that albumin
activates PDH by sequestrating free fatty acids or their
CoA derivatives (Tabernero et al., 1999). Astrocytes in-
ternalize albumin in vesicle-like structures by receptor-
mediated endocytosis (Tabernero et al., 2002). Albumin
uptake is followed by transcytosis, including passage
through the endoplasmic reticulum (ER), which is re-
quired to induce the synthesis of oleic acid. This clearly
suggests that the transcytosis of albumin includes passage
through the ER, where albumin sequestrates oleic acid,
and the whole process initiating the signal cascade for the
synthesis of oleic acid (Fig. 2).
Oleic acid was the only fatty acid synthesized by
astrocytes, suggesting that this phenomenon has a speciﬁc
purpose. In fact, the single double bond of oleic acid is
enough to sharply increase the ﬂuidity of biological mem-
Fig. 2. Differentiation of neurons promoted by oleic acid synthesized
and released by astrocytes. Albumin enters astrocyte by a receptor-
mediated mechanism reaching endoplasmic reticulum in which pro-
motes the hydrolysis and subsequent activation of sterol responding
element binding protein-1 (SREBP) that induces the expression of
sterol-CoA desaturase (SCD), a key enzyme in oleic acid (oleate)
synthesis. Oleic acid is released by astrocytes reaching neurons in which
promotes the expression of microtubule associated protein-2 (MAP-2),
a marker of dendrite growth, and of growth-associated protein-43
(GAP-43), a marker of axon growth, through the activation of protein
kinase C (PKC) and the subsequent expression of transcription factor
6 Medina and Tabernero
branes (Alberts et al., 1996). Because membrane ﬂuidity is
critical for neurons, incorporation of oleic acid-borne
phospholipids into a discrete area of the membrane could
substantially change membrane properties. In agreement
with this, oleic acid is incorporated preferentially into
neurite bases (Tabernero et al., 2001), suggesting that
increased ﬂuidity is required at the sites of newly emerging
axons or dendrites. This would facilitate the sprouting of
the membrane during neurite growth together with en-
hanced ﬂexibility for axon orientation.
Growth associate protein-43 (GAP-43) is conspicu-
ously present during brain development but its content
decreases sharply in adult life, when the presence of
GAP-43 is constrained to high-plasticity neuronal regions
or certain exclusive synapses during long-term potentia-
tion (Skene and Vira´g, 1989). Consequently, GAP-43
may play an important role in neuronal differentiation. In
support of this, the presence of oleic acid signiﬁcantly
increases the synthesis of GAP-43, which is distributed
along axonal structures (Tabernero et al., 2001). Indeed,
the presence of oleic acid leads to the aggregation of neurons
in the typical gray/white matter fashion observed in vivo. In
addition, the presence of oleic acid elongated axons, which
contacted other neurons, thus mimicking the neuronal net-
works observed in the CNS. This phenomenon is accompa-
nied by an increase in the synthesis of GAP-43, which may
play an important role in axonal build-up (Tabernero et al.,
2001). The presence of oleic acid also upregulated microtu-
bule associated protein-2 (MAP-2) a marker of dendrite
growth (Fig. 2) (Rodrı´guez-Rodrı´guez et al., 2004), suggest-
ing that oleic acid is a neurotrophic factor that promotes
dendrite sprouting. It is therefore reasonable to propose that
oleic acid promotes neuronal differentiation in culture.
LACTATE AS THE MAIN METABOLIC
SUBSTRATE FOR OLIGODENDROCYTES
Because oligodendrocytes synthesize and maintain
myelin in the CNS, these cells require metabolic substrates
for the synthesis of this specialized lipid-rich membrane
(for review, see Baumann and Pham-Dinh, 2001; Lee,
2001). In this context, we found that not only neurons and
astrocytes are able to use lactate but also oligodendro-
cytes actively utilize lactate by oxidation and lipogenesis
(Fig. 1). The rate of lactate utilization by oligodendrocytes
was thus threefold higher than that observed in astrocytes
and neurons (Sa´nchez-Abarca et al., 2001). The high rates
of lactate utilization exhibited by oligodendrocytes were
accounted for mainly by the lipogenesis rate, which was
higher than the rates observed in other neural cells
(Sa´nchez-Abarca et al., 2001). This was not unexpected
because oligodendrocytes synthesize myelin, which re-
quires active lipogenesis. It is therefore tempting to suggest
that lactate from the blood or that synthesized by astro-
cytes from glycogen can be used for oligodendrocyte
development, including myelin synthesis.
Oligodendrocytes also showed the maximum rate of
glucose utilization as compared to astrocytes and neurons
(Sa´nchez-Abarca et al., 2001). Again, oligodendrocytes
showed high rates of glucose utilization by the pathways
required for lipid synthesis. Oligodendrocytes thus exhib-
ited a high rate of lipid synthesis together with a strong
activity of the pentose phosphate pathway (Sa´nchez-
Abarca et al., 2001), which provides redox power in the
form of NADPH for lipid synthesis (Sykes et al., 1986). In
addition, oligodendrocytes showed high rates of glucose
oxidation through the pyruvate dehydrogenase-catalyzed
reaction, a compulsory step in the generation of acetyl-
CoA as a precursor for lipid synthesis. The rate of glycerol
synthesis was also high in oligodendrocytes, suggesting
that oligodendrocyte metabolism also provides glycerol for
the synthesis of glycerol-borne phospholipids (Sa´nchez-
Abarca et al., 2001). These results clearly suggest that
oligodendrocyte metabolism is designed for the synthesis
of myelin, which is a large and highly specialized lipid-
It may be concluded that lactate is an important
metabolic substrate for the brain. During adult life, it is
used as an exchangeable substrate among brain cells to
maintain energy homeostasis in the CNS, particularly dur-
ing starvation, when astrocyte glycogen must be broken
down to supply energy and carbon skeletons to neurons.
In addition, lactate may also be synthesized in astrocytes
from blood glucose to account for neuronal requirements
during synaptic activity. Finally, lactate plays a crucial role
in brain development during the perinatal period. Lactate
from the mother and that synthesized in the placenta thus
cross syncytiotrophoblast membranes through the mono-
carboxylate carrier to reach the fetal brain, which uses it as
a metabolic substrate. Lactate accumulates in fetal blood at
the end of gestation although it is metabolized rapidly
immediately after delivery. In fact, neurons, astrocytes, and
oligodendrocytes use lactate as preferential substrate, sug-
gesting that lactate is essential for brain cell proliferation
and differentiation. This may be relevant in humans, in
which the key steps of brain development occur during
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