New Concepts in Fetal and Placental
Amino Acid Metabolism’
Frederick C. Battaglia
Department of Pediatrics, Division of Perinatal Medicine,
University of Colorado Health Sciences Center, Denver 80262
ABSTRACT:
Fetal amino acid nutrition and
metabolism have been studied primarily in pregnant sheep. The umbilical uptake of amino acids
changes during gestation, but at both mid- and
late gestation the total supply exceeds that required for growth. Weight-specific protein synthetic rate decreases with increasing gestational
age, and these changes are proportional to the
changes in metabolic rate. The use of multiple
tracer methodology coupled with measurement of
net tracer fluxes into and out of fetal and placental
tissues can be used to delineate amino acid
metabolism in considerable detail. Such studies
demonstrate that even essential amino acids can
be oxidized extensively by the fetus. The oxidation
rate of leucine exceeds its rate of accretion in
tissue proteins. Glycine metabolism is unique in
several ways; there is a large umbilical uptake of
glycine without a measurable uterine uptake. In
late gestation there is no significant umbilical
uptake of serine, although there is a significant
uterine uptake, suggesting net uteroplacental utilization. Glycine is oxidized within the fetal liver
and used for serum production. The interorgan
exchange of amino acids between the fetal liver
and placenta is clearly of major importance for
serine and glycine metabolism and is likely to be
of major importance for most nonessential amino
acids.
Key Words: Placenta, Fetus, Fetal Proteins, Amino Acid Metabolism,
Nonessential Amino Acids, Branched Chain Amino Acids
J. Anim. Sci.
Introduction
The important roles of amino acids in the
normal growth and development of the mammalian fetus extend beyond the obvious requirements for protein synthesis and net protein excretion. Their multiple roles in human metabolism
have been reviewed elsewhere (Young, 1987).
Amino acids may be interconverted and in the
process act as interorgan shuttles for nitrogen or
carbon (Christensen et al., 1985; Christensen, 19901.
They may contribute to carbon accretion in the
form of carbohydrates derived from pyruvate or aketoglutarate. Amino acids are also used as
metabolic fuels by the fetus (Battaglia and
Meschia, 1988). To meet these requirements, amino
‘Presented at a symposium titled “Amino Acids in Meat
Animal Production:Current Concepts and Future Perspectives”
at the ASAS 83rd Annu. Mtg., Laramie, WY.
Received October 28, 1991.
Accepted March 3, 1992.
1992. 70:3258-3263
acids are transported across the placenta using
specific transport systems often shared by multiple amino acids (Yudilevich and Sweiry, 1985). In
this paper, I shall focus on three aspects of
perinatal amino acid metabolism: 11 the relationship between fetal protein synthetic rate and
gestational age and amino acid supply, 2) the role
of amino acids as metabolic fuels for the fetus, and
3) the interorgan exchange of some amino acids
between the placenta and fetal tissues such as the
liver and hindlimb.
Protein Synthesis and Fetal
Amino Acid Supply
Fetal protein synthetic rate has been estimated
in the fetal lamb. The absolute values for the
fractional protein synthetic rate u(,) have varied
widely in the literature, probably as a reflection of
the different tracer methodologies employed for its
estimation (Meier et al., 1981; Noakes and Young,
1981; Schaefer and Krishnamurti, 1984; Kennaugh
3258
FETAL
AND
PLACENTAL AMINO ACID
et al., 1987; Milley, 1987; Van Veen et al., 19871.
However, if the same tracer amino acid, leucine, is
employed to estimate the fetal K, at different
gestational ages, it is clear that Ks decreases with
increasing gestational age and the decrease is
greater than that of the fractional protein accretion rate (K), (Kennaugh et al., 1987; Van Veen et
al., 1987). Because protein breakdown is the difference between accretion and synthesis, it too is
decreasing sharply in late gestation. The endocrine changes responsible for the decreasing Ks
and protein turnover rate in the latter third of
gestation are not yet known. The higher fetal
protein synthetic rate a t midgestation explains, in
part, the higher metabolic rate of the midgestation
fetus. The increase in protein synthetic rate of the
midgestation fetus is proportional to the increased
fetal oxygen consumption compared with that of
the term fetus; that is, protein synthesis can
account for approximately 20% of the COz at midas well as at late gestation (Bell et al., 1985;
Kennaugh et al., 1987). The reasons for the
increased metabolic rate of the midgestation fetus
beyond that accounted for by increased protein
synthesis are unknown at present and, indeed, are
puzzling in light of studies that have shown a
decreased metabolic rate for the fetal brain at 90 d
of gestation compared with term (Gleason et al.,
1989).
At one time, the umbilical uptake of amino acids
was considered to reflect solely the exogenous
supply to the fetus; that is, the net entry of an
amino acid into the fetal umbilical circulation was
considered to be derived from the maternal
plasma pool by transplacental transport. This is
undoubtedly true for the essential amino acids,
those that cannot be synthesized by the fetus or
placenta. As we shall see, it is not an assumption
that can be applied without testing to the bulk of
the amino acids that can be synthesized within
mammalian tissues (nonessential amino acids).
The net umbilical uptake of the nonessential
amino acids could be derived from transplacental
transport and(or1 from production within the
placenta. The precursors for their placental
production may be derived from uptake from fetal
plasma and(or1 from maternal plasma. It is important to clarify which amino acids are provided to
the fetus largely by placental production rather
than by transplacental transport because, for
those amino acids, changes in placental
metabolism may have profound effects on their
rates of delivery to the fetus.
The umbilical uptake of amino acids represents
a crucial database for an understanding of fetal
amino acid metabolism. It is disappointing that
this measurement is available only for the fetal
lamb and not for other mammalian species. The
METABOLISM
3259
first measurement of amino acid umbilical uptake
was made in our laboratories many years ago
Lemons et al., 1976). Since then, a number of
studies have confirmed that most amino acids are
delivered into the fetal circulation in amounts that
exceed their net rates of excretion (Lemons and
Schreiner, 1983; Bell et al., 1989; Marconi et al.,
1989). For three amino acids, glutamate, aspartate,
and serine, there are no measurable umbilical
uptakes. In late gestation, glutamate is taken up
by the placenta from the fetal circulation. In
addition, at midgestation, serine and glutamate
are taken up by the placenta from the fetal
circulation. Thus, the fetal requirements for these
amino acids are met entirely by production within
fetal tissues.
The umbilical uptake of amino acids has been
reported to remain unchanged over a 5-d period of
maternal fasting (Lemons and Schreiner, 1984).
Even more surprising, Lemons et al. found a large
discrepancy between uterine uptake and umbilical
uptake and a large net accretion of amino acid
nitrogen in the placenta CLemons and Schreiner,
1984; Lemons et al., 19841. They postulated that
amino acids may be used as fuels by the placenta
during maternal fasting. This hypothesis has not
been tested to date. These data conflict with other
studies, which found a 75% decrease in uterine
amino acid uptake with a 5- to 7-d fast (Morriss et
al., 1980).
Recently, we have completed a detailed study of
fetal leucine metabolism using multiple-tracer
methodology (Loy et al., 19901. In late-gestation
fetal lambs, both [1-14C1and [l-13Clleucine were
infused into the fetal circulation until steady-state
enrichments were achieved, then leucine fluxes
were determined. The studies demonstrate several
interesting aspects of fetal and placental leucine
metabolism. First, even for an essential amino acid
such as leucine, there is extensive utilization as a
fetal fuel. Approximately 20 to 25% of the 1114Clleucine infused into the fetus could be accounted for as 1*C02 produced within the fetus
and delivered into the placenta. Figure 1 summarizes the [l-14Clleucinefluxes. There was no measurable oxidation of leucine within the uteroplacental tissues. However, the first step in leucine
metabolism is its reversible deamination to aketoisocaproic acid (KIC).There is a high activity
of the branched-chain amino acid (BCAAI transferase in sheep placenta. In vivo under steady-state
conditions we could demonstrate a net placental
production of KIC that entered both the umbilical
and uterine circulations. The net KIC flux to the
fetus was equal to .D pnol.kgl.min-' of fetus. In
addition to demonstrating net KIC production
within the placenta from the deamination of
leucine, the study provided excellent agreement
3260
BA'ITAGLIA
too%
6 *C,
BLOOD
- LEU
FETAL
PLACENTA
...I
?
- LEU
3B*C,
-LEU
BLOOD
-
6 *C, K I C
1'13
R e s i dual
Recovered i n
Placenta
( 6 OS*C,-LEU)
Recovered in
Carcass
(51 a r * C , - L E U 1
Figure 1. Summary of L[1-14C]-leucineinfusion and
disposal rates. All fluxes are presented as percentage of
infusion rate. Residual fluxes represent unaccounted
fractions [From Loy et al., 1990).
for two independent estimates of leucine oxidation. The total umbilical uptake of leucine plus
KIC in the fetal circulation was
4.9
p~l.kg'.min-~
The
. net accretion rate of leucine
in tissue proteins at that stage of gestation is 2
p o l - k g l min-l.
Thus,
approximately
2.9
p o l . k g ' . m i n - l of leucine was utilized in the
fetus beyond that required for protein accretion.
From the [l-14Clleucinedata and the fetal plasma
KIC enrichment, we estimated a n oxidation rate of
leucine within the fetus of 2.8 pmol.kgl.min-'.
Such internal consistency between tracer-estimated COa production vs net entry and accretion
balances for a n essential amino acid lends credence to the estimation of metabolic fluxes within
the fetal compartment using tracer methodology.
Exchange Between Fetal Tissues
and the Placenta
Thus far, only two tissue sites, fetal hindlimb
and fetal liver, have been studied in terms of the
net uptake or release of amino acids. For the
hindlimb, two different studies have described the
characteristics of hindlimb net amino acid balance
during fetal life vs that during postnatal life
(Liechty and Lemons, 1984; Wilkening et al.,
unpublished datal. During fetal life with the
pregnant ewe in the fed state, instead of a net
release of glutamine and alanine there is a net
uptake of these amino acids. The fact that fetal
hindlimb tissue shows no net alanine release
under normal fed state conditions is unexpected
given the relatively large alanine uptake by the
fetal liver. However, during maternal fasting both
maternal hindlimb tissues and fetal hindlimb
tissues demonstrate a net efflux of both alanine
and glutamine (Liechty and Lemons, 1984).
Presumably, they may then be taken up by the
fetal liver and utilized for glucose production. It
has been shown that fetal glucogenesis occurs in
the lamb under conditions associated with a
reduced umbilical glucose uptake such as occurs
during maternal fasting (Hay et al., 1981). An
increased uptake of B C M by fetal hindlimb
tissues has been reported with maternal fasting
(Liechty et al., 1987193. In the study by Liechty et al.
(1987131, the uptake of BCAA nitrogen after a
5-d fast was approximately equal to the combined
release of alanine + glutamine expressed in N
equivalents. This is consistent with increased
BCAA oxidation in fetal hindlimb during fasting
aiechty et al., 1987a). Fetal ovine skeletal muscle
has been reported to have BCAA transaminase
activity 100-foldgreater than that in adult skeletal
muscle, but its activity was unaltered in muscle by
fasting (Goodwin et al., 1987). Fetal muscle is
known to have a relatively high activity of the
enzyme BCAA dehydrogenase, whereas there is
only minimal activity of the BCAA dehydrogenase
within the sheep placenta (Loy et al., 1990). In a
recent study of leucine fluxes there was no in vivo
evidence of leucine oxidation within the placenta,
although there was a high rate of leucine oxidation by the fetus (Loy et al., 1990).
Our laboratory has reported the fetal hepatic
uptake of amino acids in late-gestation, fetal
lambs under steady-state conditions (Marconi et
al., 1989). The hepatic uptake of amino acids is of
particular interest from a nutritional standpoint
because during fetal life the umbilical blood flow
represents between 70 and 90% of fetal hepatic
blood flow. Approximately one-half of the total
umbilical blood flow enters the liver and one-half
bypasses the liver through the ductus venosus
(Edelstone et al., 19781. This fraction of umbilical
blood flow passes through the liver before entering
the inferior vena cava, an arrangement that
permits the fetal liver first-pass extraction and
metabolism of amino acids before their entry into
the systemic circulation. Figure 2 illustrates the
location of chronically implanted catheters in the
fetal circulation, which we have used for studies of
placental and fetal metabolism, the latter separated into hepatic and extrahepatic tissues. The
study by Marconi et al. (1989) demonstrated a
large hepatic uptake of all the essential and most
of the nonessential amino acids by both lobes of
the fetal liver. In fact, despite differences in
perfusion pattern of the two fetal lobes, there were
no demonstrable differences in the pattern of
arteriovenous differences for individual amino
acids across the left and right hepatic lobes.
Interestingly, glutamate and serine were not taken
up by the fetal liver, but rather were released by
the liver into the fetal circulation. The net release
3261
FETAL AND PLACENTAL AMINO ACID METABOLISM
of glutamate has been reported across the liver of
adult sheep (Heitman and Bergman, 1981) and
cows (Lomax and Baird, 1983; Huntington and
Reynolds, 1987). However, there have been no
reports of net serine release from the hepatic
circulation in any adult mammalian species. This
seems to be a rather unique feature of fetal
hepatic metabolism. It is interesting that the
pattern for glutamine and glutamate on the one
hand and for glycine and serine on the other hand
are such as to suggest a potential hepatic placental cycling for these metabolically related amino
acids. Glycine (a potential precursor of serine) and
glutamine (a potential precursor of glutamate) are
both delivered from the placenta into the fetal
circulation and taken up from the fetal circulation
into the fetal liver. In contrast, glutamate and
serine (potential metabolic products of glutamine
deamination and glycine oxidation) are released
from the fetal liver and taken up from the fetal
circulation by the placenta. These observations on
net substrate balance for these amino acids led us
to attempt to confirm the fetal hepatic production
of serine derived from glycine.
We employed the same general approach that
was used in the studies of leucine metabolism for
studies of fetal glycine metabolism. Both [1-13C1
and [l-14Clglycinewere infused as a primed constant infusion into the fetal circulation of lategestation ewes until steady-state enrichments
were achieved. At that time, net tracer fluxes into
and out of the fetal liver and of the placenta were
determined, using the basic animal preparation
illustrated in Figure 2. The study clearly demonstrated that [13Clserine and I4CO2 were produced
in the fetal liver in approximately equal amounts
from the fetal hepatic uptake of [1J3C1 and [I14Clglycine.Furthermore, the rate of glycine oxidation was appreciable. The COz production rate
from fetal plasma glycine was equal to approximately 12% of the plasma glycine disposal rate.
Interestingly, glycine oxidation seemed to be
largely a function of fetal hepatic oxidation, that
is, the 14C02produced by the fetal liver accounted
for at least 70% of the total 14C02produced within
the fetus. In contrast to leucine, there was very
little uptake of glycine from the fetal circulation
into the placenta, and we could detect no transport of tracer glycine from the fetal circulation
into the maternal uterine venous blood. Thus,
tracer glycine infused into the fetal circulation
was virtually trapped within the fetal compartment. This is in marked contrast to leucine fluxes,
for which 38% of-the [14Clleucine infused in the
fetus entered the placenta from the fetal circulation (Loy et al., 19901. Given the fact that there is a
large umbilical uptake of glycine in the order of 5
to 7 p ~ o l . k g - ~ . m i n -and
~ that a number of
investigators have been unable to demonstrate
significant glycine uptake by the pregnant uterus
from the maternal circulation (Holzman et al.,
1979; Morriss et al., 19791, the combined data
strongly support the hypothesis that a large
fraction of the glycine delivered to the fetus from
the placenta is derived by placental production.
Finally, in recent studies that we have published
thus f a r only in abstract form (Moores et al., 1990)
we have investigated serine fluxes in the midgestation fetal lamb using the same approach of a
combined infusion of [1-'3C1 and [l-14Clserine.
Although these data are still preliminary, we were
able to demonstrate two interesting features of
fetal serine metabolism that tend to support the
observations made for glycine metabolism. The
first is that we could demonstrate a large net
uptake of tracer serine into the placenta from the
fetal circulation. Accompanying the placental serine uptake, there w&s a significant net efflux of
tracer-labeled glycine from the placenta into the
fetal circulation. These data suggest that the
placenta utilizes serine derived from the fetal
plasma for glycine production and contributes to
the net glycine supplied to the fetus from the
placenta.
In summary, we have come to appreciate that
amino acids are not only used as building blocks
for protein synthesis but are extensively metabo-
maternal
fern. art.
n
femar I
I
I
UMBllCAL
UPTAKE
UTERIM
WTAKE
/
U
2
Figure 2. Diagram of the biologic preparation that
permits simultaneous measurements of umbilical, uterine, and fetal hepatic uptakes of substrates and of tracer
substrate/product analyses across these organs.
3262
BATTAGLIA
The advent of techniques for fetal blood sampling
during human pregnancy has already permitted
the confirmation of metabolic and nutritional
characteristics that were first described in large
animal research. For animal science, the production of healthy newborn animals with desired
growth characteristics requires an understanding
of both genetic and environmental factors (i.e.,
intrauterine and placental factors) that interact
throughout gestation.
AB
-
-B
-A-
C-
c-
I
2
t-
3
PLACENTA
Figure 3. Diagram of potential pathways for amino
acid transport and metabolism within the placenta. 1 =
classic transplacental transport, 2 = leucine determination to a-ketoisocaproic acid, with both contributing to
fetal uptake of leucine carbon, and 3 potential of one
amino acid such as serine used for glycine production,
which then enters the fetal circulation.
-
lized within the fetus, many of them having quite
high rates of decarboxylation. In addition to
serving as metabolic fuels, nonessential amino
acids may be interconverted from one form to
another. Because these interconversions may occur in different fetal organs and in the placenta,
they can serve as important pathways for the
shuttle of nitrogen and carbon between organs.
Finally, the studies with glycine and serine
metabolism have clearly demonstrated that some
amino acids are delivered to the fetus from the
placenta, not by classic transplacental transport
but by production within the placenta from other
carbon and nitrogen forms. Figure 3 presents
alternate pathways for the delivery of amino acids
into the fetal circulation. The supply of some
amino acids may then become dependent not only
on placental transport mechanisms but on placental metabolism as well.
Implications
It is clear that the nutritional and metabolic
characteristics of fetal development are unique
and cannot be inferred from studies in postnatal
life. Research with animals has provided the
framework around which questions about human
fetal development could be posed and addressed.
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