(Journal of Nutrition. 2000;130:974S-977S.)
© 2000 The American Society for Nutritional Sciences
Supplement
Glutamine and Glutamate Exchange between the Fetal Liver and the Placenta1
Frederick C. Battaglia
University of Colorado Health Sciences Center, Aurora, CO
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ABSTRACT
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The transport and metabolism of glutamine (GLN) and glutamate (GLU)
during fetal development exhibit unique characteristics that clearly
emphasize the importance of the interaction between the placenta and
the fetal liver. GLN is delivered into the fetal circulation at a rate
that is the highest of all the amino acids. In contrast, ~90% of
fetal plasma GLU is extracted by the placenta. Conversely, the fetal
liver has a large net output of GLU and a net uptake of GLN. We have
studied the fluxes of GLU and GLN into and out of the placenta and
fetal liver, as well as their interconversion in these organs, during
late gestation in sheep. In the fetus, 45% of GLN carbon taken up by
the liver exits as GLU; indeed, the production of GLU from GLN is
large, ~3.7 µmol/(min·kg fetus), and accounts for
virtually all of the GLU produced in the fetus. In contrast, only 6%
of GLU carbon is converted to GLN in the placenta; most of the fetal
plasma GLU taken up by this organ is converted to CO2.
Remarkably, placental GLU uptake accounts for >60% of the fetal
plasma GLU disposal rate. In some respects, the net output of GLU from
the liver in fetuses replaces the net hepatic glucose output that is
characteristic of postnatal life. We also examined GLN and GLU fluxes
in pregnant sheep during either dexamethasone-induced or
spontaneous parturition. At parturition, a striking reduction in GLU
output from the fetal liver occurred, leading to a fall in fetal
arterial GLU concentrations and a marked decrease in placental GLU
uptake. These changes were progressive as parturition advanced and
correlated with a marked decrease in progesterone output from the
pregnant uterus.
KEY WORDS: • placental uptake • fetal liver • glutamate • glutamine • parturition
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INTRODUCTION
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Despite the evidence collected in adults that glutamine
(GLN)2
and glutamate (GLU) play unique roles in nutrition and metabolism,
their functions during early development have received scant attention.
In fact, only about 20 years ago, while studying the umbilical uptake
of nutrients by the ovine fetus, did we make the initial, key
observation that the placenta takes up GLU from the fetal circulation,
while concurrently releasing GLN into the fetal circulation in very
large amounts (Lemons et al. 1976
). From this finding,
it was clear that all fetal GLU requirements must be met by the fetal
production of this amino acid.
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Net fluxes of glutamine and glutamate
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The early observation that GLU is extracted from the fetal
circulation by the placenta (Lemons et al. 1976
) was
subsequently confirmed in late-gestation ovine fetuses, both in our
laboratory and in those of others (Chung et al. 1998
,
Lemons and Schreiner 1984
, Marconi et al. 1989
). In addition, studies in rhesus monkeys of the transport
of labeled GLU from the maternal into the fetal circulation
demonstrated there to be little or no GLU transport across the primate
placenta (Stegink et al. 1975
). Others have shown in
humans during cesarean section (when both umbilical arterial and venous
blood samples can be obtained) that the fetus demonstrates a negative
(umbilical vein - fetal artery) concentration difference for GLU
across the placenta (Hayashi et al. 1978
). This finding
confirms in humans, as in other species, that there is a net uptake of
GLU from the umbilical circulation into the placenta. Hence, this
phenomenon is not unique to the epitheliochorial placenta, but seems to
be a more general characteristic of trophoblasts. Figure 1
presents data from a recent study of 18 pregnant sheep, summarizing the
umbilical and uterine uptakes of GLN and GLU (Chung et al. 1998
). Note that GLU is taken up by the placenta from both
circulations. Additionally, GLN delivery to the fetus (i.e., its
umbilical uptake) is significantly greater than uterine uptake,
demonstrating net placental GLN production. In the 1980s, fetal surgery
progressed to a point that permitted sampling of the venous drainage
from the fetal liver. The preparation we utilized is described in
Figure 2
, with potential infusion sites for tracers in both the maternal and
fetal circulations. Thus, for the first time, we were able to look at
the fluxes of amino acids into and out of the fetal liver and placenta
simultaneously. Subsequent studies using this procedure revealed the
existence of important interorgan cycles for amino acids between fetal
liver and placenta. Specifically, we observed the opposite arrangement
for GLU and GLN across the fetal liver than that across the placenta.
That is, the fetal liver experiences a large uptake of GLN from the
fetal circulation, and a large net hepatic release of GLU, a phenomenon
that is not found in normal postnatal hepatic metabolism. In essence,
we found the following: 1) the placenta delivers GLN into
the fetal circulation; 2) GLN is extracted by the fetal
liver and used for the net hepatic release of GLU; and 3)
the GLU circulating in fetal blood is taken up by the placenta.
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Figure 1. The uterine and umbilical uptakes of glutamate (Glu) and glutamine
(Gln) are presented as well as their fetal and maternal arterial
concentrations. The uptakes for each circulation were calculated as the
(flow x arteriovenous concentration difference).
*P < 0.05, ***P < 0.001
(paired t test). From Chung et al. (1998)
.
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Figure 2. Schematic of the infusion and sampling sites utilized for tracer
studies in late gestational lambs (see text). Abbreviations: A,
maternal artery sample; V, uterine vein sample; a, umbilical artery
sample; g, umbilical vein sample; h, left fetal hepatic vein; i, fetal
venous infusion; II, maternal venous infustion.
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Placental glutamate supply
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Because there is little uterine uptake of GLU, placental GLU
supply is determined by measuring placental GLU production and GLU
delivery to the placenta from the fetal circulation. The coefficient of
extraction of GLU from fetal plasma as it perfuses the placenta is
~90%, a very high value that is unique to GLU (Moores et al. 1994
). Thus, the GLU supply to the placenta is determined
primarily by the umbilical delivery rate (represented by the umbilical
plasma flow) x the fetal arterial GLU concentration. The latter
is a function of fetal hepatic GLU release. Tracer GLU and GLN studies
of the fetal lamb have shown that the hepatic production rate of
glutamate from glutamine is virtually identical to the total
fetal glutamate production rate from glutamine (Vaughn et al. 1995
). Thus, the fetal liver is the primary site for glutamate
production and, as such, also determines the glutamate supply to the
placenta.
Recent data from our laboratory suggest that the placental production
of GLU from oxoglutarate may be driven by the high rate of
transamination of the branched-chain amino acids (BCAA) to their
respective keto acids. The ovine placenta has a high level of activity
of the branched-chain transaminases, which is consistent with other
data on tracer leucine fluxes across the placenta and in the fetal
circulation. These studies have shown that ~20–25% of leucine
uptake from the maternal circulation is utilized within the placenta
(Loy et al. 1990
). The nitrogen derived from the
metabolism of BCAA into their respective keto acids contributes to both
placental NH3 production and GLU formation from
oxoglutarate (Józwik et al. 1999
). Thus,
the placental supply of GLU derives from both its uptake from the fetal
circulation and its production in the placenta associated with BCAA
transamination. Figure 3
summarizes data from several studies (Chung et al. 1998
,
Józwik et al. 1999
, Loy et al. 1991
) and indicates the net uptake or release from sheep
placenta of the BCAA, GLN and GLU into the uterine and umbilical
circulations.
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Figure 3. The net fluxes, measured in vivo, of the branched-chain amino
acids, glutamine, glutamate and ammonia, into and out of the ovine
placenta. The values are expressed in µmol/kg fetus/min. Note the
contribution of the branched-chain amino acids to both glutamate
and NH3 production within the placenta. Abbreviations: gln,
glutamine; glu, glutamate; akg,  -ketoglutarate; TCA, tricarboxylic
acid cycle; bcaa, branched-chain amino acids; aka,
branched-chain -keto acids; NH3, ammonia. From
Chung et al. (1998)
, Loy et al. (1990)
,
and Józwik et al. (1999).
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When L-[1-14C] GLU is infused into the fetal
circulation, ~80% of the carbon can be accounted for as
CO2, half in the fetus and half in the placenta
(Moores et al. 1994
). When tracer-labeled GLN is
infused into the fetal circulation, ~50% of the hepatic uptake exits
the fetal liver as GLU (Vaughn et al. 1995
). The
calculated fetal hepatic production rate of GLU from GLN is 3–4
µmol/(kg fetus·min). Both GLN and GLU (and alanine)
are taken up by fetal hindlimb tissues (Wilkening et al. 1994
). The fact that the fetal carcass, as represented by the
hind limb tissues, takes up both GLN and alanine is consistent with
data showing there to be no significant rate of fetal hepatic
gluconeogenesis (Hay et al. 1984
). GLU delivery to the
carcass and placenta comes primarily from the fetal liver and
indirectly via GLN delivery from the placenta.
In one sense, the large GLU output from the fetal liver can be equated
with the large hepatic glucose output during postnatal life. We have
shown that there is no significant gluconeogenesis nor any
significant glucose output from the fetal liver during normal gestation
(Hay et al. 1984
). This is presumably useful to the
fetus because fetal glucose production would block the transplacental
transport of glucose from the maternal to the fetal circulation.
Figure 4
summarizes the carbohydrate exchange among the fetal liver, placenta
and carcass taken from recent data (Timmerman et al., unpublished
results) and Wilkening et al. (1994)
.
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Figure 4. The exchange of glucose, lactate and pyruvate among the liver,
placenta, and carcass in the fetal lamb. The data for the carcass
are calculated from measured values for the fetal hindlimb. PYR
= P = pyruvate, LAC = L = lactose, G = glucose. [Timmerman et al.,
unpublished observations, and Wilkening et al. (1994)
].
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Changes in glutamine-glutamate metabolism during parturition
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During parturition, endocrine changes occur in the fetal
circulation that signal a shift from the fetal to the postnatal pattern
of net hepatic glucose or GLU release. For this reason, we thought it
would be instructive to study net hepatic and placental uptake and/or
release of GLN and GLU around the time of parturition. To facilitate
these studies, we used a fetal infusion of dexamethasone to induce
labor in late-gestational fetal lambs (Barbera et al. 1997
). The arteriovenous concentration differences for GLN and
GLU were measured in a control period that preceded dexamethasone
infusion, and then at 25 h and at 40–48 h after dexamethasone
infusion began. At 25 h, GLU release from the fetal liver had
fallen dramatically from 180 ± 56 to 45 ± 18
µmol/mmol O2. This change produced a
significant fall in fetal plasma GLU concentrations and led to a
significant decline in placental GLU uptake from the fetal plasma
(arteriovenous differences across the umbilical circulation fell from
control values of 18 ± 3 to 2 ± 3 µmol/mmol
O2). At the same time, progesterone output from
the pregnant uterus also decreased significantly. Thus, the events
leading up to parturition are associated with profound changes in fetal
hepatic and placental GLU and GLN metabolism. However, with the use of
this paradigm, we could not distinguish whether these changes were due
to the many endocrine changes associated with parturition or simply to
the dexamethasone used to induce parturition.
Our ongoing studies are attempting to clarify this latter issue, but at
present are very preliminary. One study examined fetal hepatic and
placental GLU and GLN metabolism during spontaneous parturition
(Timmerman et al., unpublished observations). The experimental design
enables us to sample the fetal circulation, including the hepatic
venous circulation and the maternal uterine circulation, beginning
7–10 d before expected parturition. The results to date have revealed
both similarities to and differences from dexamethasone-induced
parturition. The similarities relate to changes in GLU and progesterone
metabolism. During spontaneous parturition, there is a marked decrease
in net fetal hepatic GLU output, leading to a decrease in placental GLU
uptake from the fetal circulation (see Fig. 5
, which presents data for a single animal). Coincident with these
changes, progesterone output from the maternal uterus decreases.
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Figure 5. Changes in fetal hepatic and placental glutamate (glu) uptake before
parturition. The data are derived from a single animal for GLU release
from the fetal liver and GLU uptake by the placenta. (Timmerman et al.,
unpublished observations).
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A second preliminary study examined whether GLN carbon flux within the
fetal liver is altered during parturition (Timmerman et al.,
unpublished observations). We utilized the model of
dexamethasone-induced parturition to study the fluxes of
L-[1-13C] GLN and
L-[3H4+3H5]
GLU in the fetal circulation. These fluxes were measured in each animal
before and after a 25-h fetal infusion of dexamethasone. The most
significant finding was that the ratio of
13CO2 to GLUm +
1 leaving the fetal liver was significantly higher during
the dexamethasone infusion compared with a control period. Thus, GLN
carbon is redirected into oxoglutarate and the tricarboxylic acid cycle
and away from GLU release.
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SUMMARY
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Glutamine and GLU metabolism play important and unique
roles during fetal development. Their interorgan exchange (between
fetal liver and placenta) and particularly, the fetal liver’s central
role in maintaining GLU supply to the placenta, illustrate that these
two organs form an integrated organ system in early development.
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FOOTNOTES
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1 Presented at the International Symposium on
Glutamate, October 12–14, 1998 at the Clinical Center for Rare
Diseases Aldo e Cele Daccó, Mario Negri Institute
for Pharmacological Research, Bergamo, Italy. The symposium was
sponsored jointly by the Baylor College of Medicine, the Center for
Nutrition at the University of Pittsburgh School of Medicine, the
Monell Chemical Senses Center, the International Union of Food Science
and Technology, and the Center for Human Nutrition; financial support
was provided by the International Glutamate Technical Committee. The
proceedings of the symposium are published as a supplement to
The Journal of Nutrition. Editors for the symposium
publication were John D. Fernstrom, the University of Pittsburgh School
of Medicine, and Silvio Garattini, the Mario Negri Institute for
Pharmacological Research. 
2 Abbreviations used: BCAA, branched-chain
amino acid; GLN, glutamine; GLU, glutamate.
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REFERENCES
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1.
Barbera A., Wilkening R., Battaglia F. C., Meschia G. Metabolic alterations in the fetal hepatic and umbilical circulations during glucocorticoid induced parturition in sheep. Pediatr. Res. 1997;41:242-248[Medline]
2.
Chung M., Teng C., Timmerman M., Meschia G., Battaglia F. C. Production and utilization of amino acids by ovine placenta in vivo. Am. J. Physiol. 1998;274:E13-E22[Abstract/Free Full Text]
3.
Hay W. W., Jr, Sparks J. W., Wilkening R. B., Battaglia F. C., Meschia G. Fetal glucose uptake and utilization as functions of maternal glucose concentration. Am. J. Physiol. 1984;246:E237-E242[Abstract/Free Full Text]
4.
Hayashi S., Sanada K., Sagama N., Yamada N., Kido K. Umbilical vein-artery differences of plasma amino acids in the last trimester of human pregnancy. Biol. Neonate 1978;34:11-18[Medline]
5.
Józwik M., Teng C., Battaglia F. C, Meschia G. Fetal supply of amino acids and aminonitrogen following maternal infusion of amino acids into pregnant sheep. Am. J. Obstet. Gynecol. 1999;180:447-453[Medline]
6.
Lemons J. A., Schreiner R. L. Metabolic balance of the ovine fetus during the fed and fasted states. Ann. Nutr. Metab. 1984;28:268-280[Medline]
7.
Lemons J. A., Adcock E. W., III, Jones M. D., Jr, Naughton M. A., Meschia G., Battaglia F. C. Umbilical uptake of amino acids in the unstressed fetal lamb. J. Clin. Investig. 1976;58:1428-1434
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Loy G. L., Quick A. N., Jr, Battaglia F. C., Meschia G., Fennessey P. V. Measurement of leucine and -ketoisocaproic acid fluxes in the fetal/placental unit. J. Chromatogr. Biomed. Appl. 1991;562:169-174
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Loy G. L., Quick A. N., Jr, Hay W. W., Jr, Meschia G., Battaglia F. C., Fennessey P. V. Feto-placental deamination and decarboxylation of leucine. Am. J. Physiol. 1990;259:E492-E497[Abstract/Free Full Text]
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Marconi A. M., Battaglia F. C., Meschia G., Sparks J. W. A comparison of amino acid arteriovenous differences across the liver, hindlimb and placenta in the fetal lamb. Am. J. Physiol. 1989;257:E909-E915[Abstract/Free Full Text]
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Moores R. R., Jr, Vaughn P. R., Battaglia F. C., Fennessey P. V., Wilkening R. B., Meschia G. Glutamate metabolism in the fetus and placenta of late gestation sheep. Am. J. Physiol. 1994;267:R89-R96[Abstract/Free Full Text]
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Stegink L. D., Pitkin R. M., Reynolds W. A., Filer L. J., Jr, Boaz D. P., Brummel M. C. Placental transfer of glutamate and its metabolites in the primate. Am. J. Obstet. Gynecol. 1975;122:70-78[Medline]
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Vaughn P. R., Lobo M., Battaglia F. C., Fennessey P., Wilkening R., Meschia G. Glutamine-glutamate exchange between placenta and fetal liver. Am. J. Physiol. 1995;268:E705-E711[Abstract/Free Full Text]
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Wilkening R. B., Boyle D. W., Teng C., Meschia G., Battaglia F. C. Amino acid uptake by the fetal ovine hind limb under normal and euglycemic hyperinsulinemic states. Am. J. Physiol. 1994;266:E72-E78[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
