Placental Transport in Response to Altered Maternal Nutrition

Abstract

The mechanisms linking maternal nutrition to fetal growth and programming of adult disease remain to be fully established. We review data on changes in placental transport in response to altered maternal nutrition, including compromized utero-placental blood flow. In human intrauterine growth restriction and in most animal models involving maternal undernutrition or restricted placental blood flow, the activity of placental transporters, in particular for amino acids, is decreased in late pregnancy. The effect of maternal overnutrition on placental transport remains largely unexplored. However, some, but not all, studies in women with diabetes giving birth to large babies indicate an upregulation of placental transporters for amino acids, glucose and fatty acids. These data support the concept that the placenta responds to maternal nutritional cues by altering placental function to match fetal growth to the ability of the maternal supply line to allocate resources to the fetus. On the other hand, some findings in humans and mice suggest that placental transporters are regulated in response to fetal demand signals. These observations are consistent with the idea that fetal signals regulate placental function to compensate for changes in nutrient availability. We propose that the placenta integrates maternal and fetal nutritional cues with information from intrinsic nutrient sensors. Together, these signals regulate placental growth and nutrient transport to balance fetal demand with the ability of the mother to support pregnancy. Thus, the placenta plays a critical role in modulating maternal–fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring.

Full text

Journal of Developmental Origins of Health and Disease (2013), 4(2), 101–115.
&Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012
doi:10.1017/S2040174412000529
REVIEW
Placental transport in response to altered maternal
nutrition
F. Gaccioli, S. Lager, T. L. Powell and T. Jansson*
Department of Obstetrics and Gynecology, Center for Pregnancy and Newborn Research, University of Texas Health Science Center,
San Antonio, TX, USA
The mechanisms linking maternal nutrition to fetal growth and programming of adult disease remain to be fully established. We review data on
changes in placental transport in response to altered maternal nutrition, including compromized utero-placental blood flow. In human
intrauterine growth restriction and in most animal models involving maternal undernutrition or restricted placental blood flow, the activity of
placental transporters, in particular for amino acids, is decreased in late pregnancy. The effect of maternal overnutrition on placental transport
remains largely unexplored. However, some, but not all, studies in women with diabetes giving birth to large babies indicate an upregulation of
placental transporters for amino acids, glucose and fatty acids. These data support the concept that the placenta responds to maternal
nutritional cues by altering placental function to match fetal growth to the ability of the maternal supply line to allocate resources to the fetus.
On the other hand, some findings in humans and mice suggest that placental transporters are regulated in response to fetal demand signals. These
observations are consistent with the idea that fetal signals regulate placental function to compensate for changes in nutrient availability. We propose
that the placenta integrates maternal and fetal nutritional cues with information from intrinsic nutrient sensors. Together, these signals regulate
placental growth and nutrient transport to balance fetal demand with the ability of the mother to support pregnancy. Thus, the placenta plays a
critical role in modulating maternal–fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring.
Received 13 May 2012; Revised 10 June 2012; Accepted 5 July 2012; First published online 31 July 2012
Key words: fetal programming, maternal–fetal exchange, obesity, pregnancy, trophoblast
Introduction
Maternal nutrition has a profound impact on fetal development
and growth and influences the future health of the offspring.
1,2
However, the mechanisms linking altered maternal nutrition
to changes in fetal growth and developmental programming
are poorly understood. Previous studies in rodents and sheep
implicate changes in placental growth, structure and function as
critical mediators of adverse pregnancy outcomes when maternal
nutrient availability is altered.
3–9
Here, we review changes in
placental nutrient transport in response to altered maternal
nutrition in pregnant women and in relevant animal models.
The concept of maternal nutrition is defined broadly as the
ability of the maternal supply line to provide nutrients and
oxygen to the placenta. Our discussion will therefore also
include placental responses to compromized utero-placental
blood flow, maternal hypoxia and iron deficiency.
The placental barrier and factors influencing
placental transfer
Fetal nutrient and oxygen availability depend on the rate of
transfer across the ‘placental barrier’. In the human term placenta,
there are only two cell layers separating fetal and maternal
circulations; the fetal capillary endothelium and the syncy-
tiotrophoblast (Fig. 1).
10
The syncytiotrophoblast is the
transporting epithelium of the human placenta and has two
polarized plasma membranes: the microvillous plasma mem-
brane (MVM) directed toward maternal blood in the inter-
villous space and the basal plasma membrane (BPM) facing the
fetal capillary. In the mouse and rat placenta, three trophoblast
layers form the placental barrier, and accumulating evidence
suggests that the maternal-facing plasma membrane of tropho-
blast layer II of the mouse placenta is functionally analogous to
the MVM in the human placenta.
11
In the hemochorial placenta
of primates and rodents, the trophoblast is directly in contact
with maternal blood. However, in the synepitheliochorial pla-
centa of the sheep the maternal capillary endothelium and
uterine epithelium remain intact and fetal binucleate cells
migrate and fuse with the uterine epithelium, creating a syncy-
tium of mixed maternal and fetal origin.
12,13
Net maternal–fetal transfer is influenced by a multitude of
factors. These include utero-placental and umbilical blood flows,
available exchange area, barrier thickness, placental metabolism,
concentration gradients and transporter expression/activity in
the placental barrier. Placental transfer of highly permeable
molecules such as oxygen is non-mediated and particularly
influenced by changes in barrier thickness, concentration
gradients, placental metabolism and blood flow.
14
In contrast,
the rate-limiting step for maternal–fetal transfer of many ions
*Address for correspondence: Dr T. Jansson, Department of Obstetrics
and Gynecology, Center for Pregnancy and Newborn Research, University
of Texas Health Science Center, Mail Code 7836, 7703 Floyd Curl Drive,
San Antonio, TX 78229-3900, USA.
(Email jansson@uthscsa.edu)

and nutrients, such as amino acids, is the transport across the
two plasma membranes of the syncytiotrophoblast, which
express a large number of transporter proteins. Thus, changes in
expression or activity of placental nutrient and ion transporters
in response to altered maternal nutrition may influence fetal
nutrient availability and growth. Regulation of placental nutrient
transporters may therefore constitute a link between maternal
nutrition and developmental programming.
In this review, we will focus on changes in transporter
activity determined in vitro and transplacental transport
measured in vivo. Furthermore, we will discuss factors cir-
culating in maternal and fetal blood and placental signaling
pathways that have been shown to regulate key placental
nutrient transporters. A detailed discussion of general
mechanisms of maternal–fetal exchange, placental blood flow,
metabolism, energy availability and ion gradients, all factors
affecting placental transport indirectly, is beyond the scope of
this paper and have been reviewed elsewhere.
15–18
Placental transport in response to maternal
undernutrition: two models
There are two fundamentally different, but not mutually
exclusive, models for how the placenta responds to changes in
maternal nutrition (Fig. 2). In the placental nutrient sensing
model,
3,8,19
the placenta responds to maternal nutritional
cues, resulting in downregulation of placental nutrient
transporters in response to maternal undernutrition or
restricted utero-placental blood flow. As a result, fetal nutri-
ent availability is decreased and intrauterine growth restric-
tion (IUGR) develops (Fig. 2). Placental nutrient sensing
therefore represents a mechanism by which fetal growth is
matched to the ability of the maternal supply line to allocate
resources to the fetus. In this model, changes in placental
growth and nutrient transport directly contribute to or cause
altered fetal growth. On the other hand, predominantly based
on elegant mouse studies it has been proposed that placental
function is primarily controlled by fetal demand.
20–22
In response to maternal undernutrition or restricted utero-
placental blood flow, resulting in decreased placental transfer
and limited fetal nutrient availability, the fetal demand model
predicts that the fetus signals to the placenta to upregulate
placental growth and nutrient transport (Fig. 2). This model
represents a classical homeostatic mechanism by which the
fetus compensates for changes in nutrient availability by
regulating nutrient supply (i.e. placental transport) in the
opposite direction.
In the subsequent sections, we will discuss the evidence for
these two models and explore maternal and fetal nutritional cues
that may be important regulating placental growth and nutrient
transport. Subsequently, we will present a model in which fetal
demand and placental nutrient sensing are integrated.
Decreased maternal nutrient availability
There is a wealth of information on the impact of impaired
placental blood flow on placental transport functions in
humans. However, no studies are available exploring the
effects of maternal undernutrition on placental transport in
pregnant women. In contrast, the placental response to
maternal nutrient restriction has been investigated in some
detail in animal models.
Studies in humans
In general, maternal undernutrition throughout pregnancy
inhibits placental growth as shown by detailed studies of
pregnancy outcomes during and after the Dutch famine
1944–1945.
23
However, maternal undernutrition restricted
to first trimester resulted in increased placental weight at
term.
23
The effects of maternal dietary restriction on placental
transport in pregnant women are unknown. In contrast, there
is an abundance of data, predominantly obtained in vitro,
describing changes in placental transport capacity in pregnancies
complicated by IUGR (Table 1).
19,24–26
In most of these studies, IUGR was caused by ‘placental
insufficiency’, suggesting that the primary defect might have
been a failure in the normal increase of utero-placental blood
flow with advancing gestation. A subgroup of IUGR fetuses are
Fig. 1. The placental barrier in the human term placenta. The figure
represents a cross-section of the human placenta. The insert to the
right shows a schematic illustration of the placental barrier, which at
term mainly consists of the syncytiotrophoblast (ST) cell and the
fetal capillary (FC) endothelial cell. Of these structures, it is primarily
the two polarized syncytiotrophoblast plasma membranes, the
microvillous plasma membrane (MVM) and the basal plasma
membrane (BPM) that restrict the transfer of molecules like ions and
amino acids. N, nucleus of syncytiotrophoblast cell; IVS, intervillous
space;SA,spiralartery;VT,villoustree;UC,umbilicalcord.
Reproduced by permission from Elsevier Ltd.
102 F. Gaccioli et al.

hypoglycemic in utero,
41
however, this appears not to be
due to a decreased transport capacity for glucose across the
placental barrier.
28,35
In contrast, restricted fetal growth due to
maternal hypoxemia at high altitude may be associated with
decreased placental glucose transport capacity, as indicated
by downregulation of glucose transporter (GLUT) expression
in BPM.
42
System A is a Na
1
-dependent transporter mediating the
cellular uptake of non-essential neutral amino acids.
43
System
A activity establishes the high intracellular concentration
of amino acids like glycine, which is used to exchange for
extracellular essential amino acids via System L. Thus, System
A activity is critical for placental transport of both non-
essential and essential amino acids. System A activity has
consistently been reported to be decreased in the MVM, the
rate-limiting step in transplacental amino acid transfer, iso-
lated from IUGR placentas.
27–30
Furthermore, the most
severe cases of IUGR, as defined by abnormal pulsatility
index in the umbilical artery and abnormal fetal heart rate
tracings, are associated with the most pronounced decreases in
MVM System A activity.
29
In contrast to these findings in
‘idiopathic’ IUGR, Shibata et al.
44
reported that placental
System A activity, as measured in villous explants, was not
altered in placentas of small-for-gestational age (SGA) babies
in pregnancies complicated by preeclampsia.
The mechanisms underlying these interesting differences
between IUGR/SGA pregnancies with and without pre-
eclampsia remain to be established. However, the difference
may be related to the observation that preeclampsia is char-
acterized by increased maternal levels of hormones, including
insulin and leptin, which are well established to stimulate
placental System A activity in vitro.
45,46
A recent report
demonstrated that homocysteine is a competitive inhibitor of
System A transport.
47
Thus, despite the unchanged in vitro
System A activity in placentas of SGA babies from pregnancies
complicated by preeclampsia,
44
it is possible that increased
Fig. 2. Placental nutrient transport in response to maternal undernutrition: two models. Schematic representation of the two models
proposed for the regulation of placental function in response to maternal undernutrition (see text for details). The fetal demand model
(bottom) predicts that the fetus signals to the placenta to upregulate placental growth and nutrient transport to meet fetal nutritional
demands. In the placental nutrient sensing model (top), the placenta responds to maternal nutritional cues, resulting in downregulation of
placental nutrient transporters, which leads to decreased fetal nutrient availability and intrauterine growth restriction.
Table 1. Placental transport in human IUGR
Transport system MVM BPM References
System A k2
27–30
System L kk
31
System bk2
32,33
Lysine 2k
31,34
Glucose 22
28,35
Lipoprotein lipase knd
36
Ca
21
ATPase nd m
37
Na
1
/H
1
exchanger knd
29,38
Lactate 2k
39
Na
1
/K
1
ATPase k2
40
IUGR, intrauterine growth restriction; MVM, microvillous
plasma membrane; BPM, basal plasma membranes; nd, not
determined.
Increased (m), unaltered (2) or reduced (k) transporter activity
in MVM and BPM isolated from human pregnancies complicated
by IUGR at term as compared with appropriate-for-gestational age
controls.
Maternal nutrition and placental transport 103

circulating maternal levels of homocysteine observed in this
syndrome may decrease placental System A activity in vivo.
The activities of transporters of essential amino acids, such
as System b(transporting taurine) and System L (mediating
the uptake of a range of essential amino acids including
leucine) are reduced in MVM and/or BPM isolated from
IUGR placentas (Table 1). These in vitro findings are con-
sistent with stable isotope studies in pregnant women
demonstrating that placental transfer of the essential amino
acids leucine and phenylalanine is reduced in IUGR at
term.
48,49
Furthermore, a reduced placental capacity to
transport amino acids is in agreement with studies showing
reduced circulating amino acids, in particular essential amino
acids, in IUGR fetuses.
50–52
The activity of MVM lipopro-
tein lipase (LPL), which mediates the first critical step in
transplacental transfer of free fatty acids (FFA), is reduced in
IUGR.
36
These data are in line with clinical studies showing
lower fetal/maternal plasma ratios for long-chain poly-
unsaturated fatty acids (LCPUFAs) in IUGR.
53
Key placental ion transporters are also affected when fetal
growth is restricted. The activities of Na
1
/K
1
-ATPase, the
Na
1
/H
1
exchanger and lactate transporters are down-
regulated in IUGR.
29,38–40
These membrane transport sys-
tems are involved in pH regulation, vectorial Na
1
transport
and maintenance of the Na
1
gradient that drives the transport
of other vital nutrients such as amino acids. Some ions, however,
appear to be regulated quite differently. In particular, Ca
21
-
ATPase is upregulated in BPM isolated from IUGR placentas.
37
In summary, these studies show a downregulation of key
placental transporters for amino acids, lipids and ions in
human IUGR. However, most of these studies were per-
formed at term, or in a few cases using tissue obtained from
pre-term deliveries in third trimester,
28,38
and it is possible
that compensatory changes consistent with fetal demand
signals may be present earlier in pregnancy. Furthermore, the
distinct upregulation of BPM Ca
21
-ATPase activity in IUGR
placentas
37
may represent a compensatory activation of the
placental calcium transport system stimulated by an increased
fetal demand. Despite these caveats, the available information
from IUGR in humans is in general agreement with the
placental nutrient sensing model for regulation of placental
transporters.
Studies in animal models
The effect of maternal undernutrition on placental growth in
animal models appears to depend on the species under study
and the timing, duration, type and degree of nutrient
restriction. For example, in sheep, a 50% calorie restriction
during the first half of pregnancy increased placental weights
at term.
54
Similarly, a 50% reduction in protein intake in rats
starting 2 weeks before pregnancy and maintained through-
out gestation resulted in higher placental weights close to
term.
55
In contrast, 30% calorie restriction throughout
pregnancy in the baboon reduced placental weights by 18%
near term.
56
Similarly, 40% calorie restriction from gesta-
tional days (GDs) 25 to 65 in the guinea pig,
57
50%
reduction in calorie intake in the second half of pregnancy in
the rat
58
and 75% protein restriction in the rat caused pla-
cental growth restriction.
3,4
Studies in the non-human primate and in the rat indicate that
maternal undernutrition downregulates placental nutrient
transporter expression and activity. Preliminary observations
show that 30% global maternal nutrient restriction from GD 30
in the baboon results in downregulation of MVM amino acid
and GLUT isoforms close to term (GD 165, term 5184) and
decreased circulating fetal levels of essential amino acids.
59
A number of studies in the rat, employing in vivo measurements
of transplacental transfer of isotope-labeled substrate analogs,
have shown that placental capacity to transport neutral amino
acids and glucose in response to calorie or protein restriction is
decreased in late pregnancy.
60–63
In contrast, Ahokas et al.
64
found no significant change in in vivo placental amino acid
transport near term in rats subjected to 50% calorie restriction.
However, other investigators using a similar protocol have
reported downregulation of placental GLUT3
65,66
and sodium-
dependent neutral amino acid transporter (SNAT)1 and 2
protein expression
65
and upregulation of placental SNAT4
protein expression.
65
Protein restriction in pregnant rats have been shown to
decrease the in vitro activity of specific placental amino acid
transporters close to term.
4
Using the same model, we studied
placental transport in the unstressed chronically catheterized
animal at GDs 15, 18, 19 and 21 (term at GD 23), and
reported that downregulation of the placental System A
transporter activity precedes the occurrence of IUGR.
3
These
findings suggest that, in this model, decreased placental
amino acid transport is a cause of IUGR, rather than a con-
sequence. Furthermore, MVM protein expression of specific
System A (SNAT1 and 2) and System L (LAT1 and 2) amino
acid transporter isoforms was decreased in response to a low-
protein diet.
8
In contrast, maternal protein restriction did not
affect placental glucose transport.
3
Notably, downregulation of
placental amino acid transport was observed at GD 19, and
there was no evidence of compensatory upregulation before this
gestational age.
3,8
These data indicate that fetal demand signals
may not be present in this model, at least not from GD 15 and
onwards. Overall, these observations in the baboon and rat are
consistent with the placental nutrient sensing model for regulation
of placental transporters.
A series of studies in mice have provided evidence for
compensatory upregulation of placental nutrient transporters
in response to maternal undernutrition.
67–69
A 20% reduc-
tion in calorie intake from embryonic day (E)3 resulted in
decreased placental but not fetal weight at E16 and reductions
in both placental and fetal weights at E19. Placental gene
expression of GLUT1 was decreased at E16, but increased
at E19. At E19, placental gene expression of SNAT2 was
found to be increased but SNAT4 gene expression was
decreased.
67,68
Whereas placental transport capacity for glucose
104 F. Gaccioli et al.

was maintained at E16 and E19, placental capacity to
transport neutral amino acids was increased at E19.
67,68
In
addition, Coan et al.
69
explored the effect of a moderate
(222%) and severe (261%) reduction in protein intake on
placental transport function in mice in vivo. Whereas pla-
cental capacity to transport glucose was increased at E16 in
both protein restriction groups, at E19 it was elevated only in
the group subjected to severe protein restriction. In contrast,
placental amino acid transport capacity was unchanged at E16
but decreased in the moderate protein restriction group at E19.
Placental gene expression of GLUT1 was increased at E16 in the
moderate, but not in the severe, protein restriction group, but
was unaltered at E19. At E16 placental gene expression of
SNAT2 was found to be increased in the severe protein
restriction group, whereas at E19, SNAT1 gene expression was
decreased in the severe restriction group and SNAT4 gene
expression was reduced in both protein restriction groups.
69
These studies suggest that placental nutrient transport appears to
be regulated differently by maternal undernutrition in the mouse
as compared with the non-human primate and the rat.
The distinct placental responses to maternal undernutrition
in the mouse and the rat could reflect true species differences,
but may also be related to subtle differences in the feeding
paradigms. In addition, the tracer methodology used in all
these studies is sensitive to differences in circulating con-
centrations of the endogenous substrate for the transporter
under study. Thus, the marked hypoglycemia (27–58% lower
glucose levels than controls) reported for mice subjected to
20% calorie restriction
67,68
or moderate/severe protein restric-
tion,
69
as well as a 32% reduction in maternal a-amino nitrogen
in response to calorie restriction,
67
could result in significant
overestimation of transplacental transport of glucose and amino
acids. Collectively, these studies in the mouse are in general
agreement with the model that fetal demand signals play an
important role in modulating placental nutrient transport in
response to changes in maternal nutrition.
Because compromized utero-placental blood flow is believed
to be involved in many clinical cases of IUGR secondary to
placental insufficiency,
70
fetal outcomes and developmental
programming have been extensively studied in animal models of
restricted utero-placental blood flow. In some of these studies,
placental transport functions have been assessed. Uterine artery
ligation in the rat resulted in IUGR and decreased transplacental
transport of glucose and amino acids in vivo.
71
In contrast,
neither the activity of the System A transporter measured in vitro
in the maternal-facing plasma membrane of rat syncytio-
trophoblast
72
nor the placental expression of GLUT1 and
GLUT3
73
werealteredinthismodel.Inguineapigs,weper-
formed unilateral uterine artery ligation in mid-pregnancy
(GD 35) and determined placental blood flows and transport of
neutral amino acids and glucose at GDs 44, 50 and 63 (term
at GD 68) in chronically catheterized non-stressed animals.
74
At GD 44, modest IUGR was observed and placental capacity
to transfer glucose and amino acids was maintained, whereas
IUGR was more severe and placental capacity to transport
amino acids was decreased at GD 50 and 63.
74
Saintonge and
Rosso
75
studied placental blood flow and placental transport
in relation to normal variations in fetal and placental growth in
the guinea pig. They reported that placental capacity to trans-
port glucose and amino acids was maintained over the range
of fetal weights with the important exception of the smallest
fetuses in which placental capacity to transport amino acids was
decreased.
75
Naturally occurring ‘runts’ in the guinea pig
therefore have the same decrease in placental amino acid
transport capacity as experimentally induced IUGR.
74
These
observations are in contrast to intra-litter variations in placental
nutrient transport and fetal growth in mice, where placental
amino acid transport capacity and SNAT2 expression have been
reported to be increased in the smallest placentas.
76
There are numerous approaches to induce IUGR in the
sheep.Amodelinvolvingexposureoftheewetohighambient
temperature, which decreases utero-placental blood flow and
placental growth resulting in asymmetric IUGR, resembles
placental insufficiency in humans.
77
Because maternal and fetal
vessels in the sheep are accessible to chronic catheterization,
allowing for precise measurements of nutrient fluxes across the
placenta, a body of information on placental nutrient transport
in this model is available. For example, the placental capacity to
transport glucose,
78
leucine,
79
threonine
80
and aminocyclo-
pentane-1-carboxylic acid (ACP)
81
(a branched-chain amino
acid analog) is reduced in this IUGR model. Taken together,
studies of utero-placental insufficiency and IUGR in a range
of animal models show that placental nutrient transport is
downregulated. These findings are reminiscent of the human
data and support the placental nutrient sensing model.
Effects of altered levels of micronutrients on placental
transport have received little attention, with the possible
exception of maternal iron deficiency, which results in mater-
nal and fetal anemia and IUGR.
82,83
However, fetal anemia
typically is less severe than maternal anemia suggesting com-
pensatory mechanisms, possibly at the placental level. Indeed,
maternal iron deficiency in the rat results in upregulation of the
placental transferrin receptor, which is expressed in the tropho-
blast maternal-facing plasma membrane and mediates iron uptake
into the placenta. Furthermore, maternal iron deficiency increases
the expression of placental divalent metal transporter 1 (DMT1),
which transports iron out of the lysosome into the cytoplasm of
the trophoblast.
84
It is likely that iron itself represents the signal
mediating these changes in placental expression because iron-
responsive elements are present in both the transferrin receptor
and DMT1 genes. However, whether other signals, such as local
hypoxia or signals originating in the fetus, are also involved
remain to be established.
Increased maternal nutrient availability
Most human and animal studies of the effect of increased
maternal nutrient availability on placental transport have been
focused on diabetes, whereas maternal obesity has attracted
much less attention.
Maternal nutrition and placental transport 105

Studies in humans
Diabetes in pregnancy, especially if poorly controlled, is
associated with intermittently elevated maternal levels of
glucose, amino acids and FFA and can therefore be regarded
as a condition of increased nutrient availability. Although
many studies in pregnant women with diabetes indicate an
increased placental capacity to transfer nutrients, data is less
consistent than for decreased maternal nutrient availability.
Pregnancy can be complicated by type 1, type 2 or gestational
diabetes (GDM), and of these conditions GDM is the most
common affecting 2–10% of all pregnancies in the United
States. However, the prevalence of GDM is expected to
increase by two- to three-fold if the new diagnostic criteria
of the Hyperglycemia and Adverse Pregnancy Outcome
study is fully adopted.
85
With the exception of subgroups
of women with type-1 diabetes who develop vascular
complications, diabetes in pregnancy, in particular GDM, is
associated with fetal overgrowth.
85
Placental nutrient trans-
port capacity in diabetes associated with fetal overgrowth
has been studied in isolated syncytiotrophoblast plasma
membranes (Table 2).
Available data on trophoblast amino acid transporter
activities in pregnancies complicated by maternal diabetes are
inconsistent. Dicke and Henderson
92
found no differences in
the uptake of neutral amino acids into MVM isolated from
GDM pregnancies as compared with controls, however, these
subjects did not give birth to larger babies. System A amino
acid transport activity was reduced and System L transport
activity unaltered in MVM isolated from pregnancies with
type-1 diabetes and fetal overgrowth.
87
In contrast, we found
that the activity of MVM System A transporter was increased
in type-1 diabetes, independent of fetal overgrowth, and
placental transport of leucine was increased in GDM.
86
These
discrepant findings may be related to differences in metho-
dology or in study populations. Notably, although birth
weights were similar in the two latter reports, placental
weights were 100–300 g higher in the diabetic groups in the
Swedish study.
86
This may indicate that the two study
populations differ in some fundamental way with regard to,
for example, ethnicity, nutrition or clinical management.
BPM glucose transport activity and GLUT1 expression are
increased in type-1 diabetes,
89,90
which could enhance pla-
cental glucose transport even during normoglycemia. Indeed,
these changes have been proposed to contribute to fetal
overgrowth in type-1 diabetes with apparent optimal glucose
control.
89
Recently, it was reported that the protein expres-
sion of GLUT9 is upregulated in MVM and BPM isolated
from placentas of women with diabetes,
93
adding to the
evidence of increased placental glucose transport capacity in
this pregnancy complication. On the other hand, using pla-
cental lobuli perfused in vitro, Osmond et al.
94
showed that
placental glucose transport was decreased in GDM pregnan-
cies with normal fetal growth; however, these changes were
normalized in GDM women treated with insulin.
95
It has
been suggested that GLUT abundance in the placental barrier
does not affect transplacental glucose transport because glu-
cose uptake varies with placental and umbilical blood flow.
96
Notwithstanding that changes in blood flow can alter placental
glucose transport, this view may be too simplistic. BPM has
much lower surface area and GLUT1 expression as compared
with MVM, and it has therefore been proposed that the transfer
across BPM, at least to some extent, limits the diffusion of
glucose across the barrier.
35
Therefore, with all other factors kept
constant, any alterations in GLUT expression/activity in the
BPM is likely to alter glucose flux across the barrier.
Maternal lipoproteins are the predominant source for fetal
supply of FFA. Triglyceride hydrolases in the MVM of the
syncytiotrophoblast release FFA from maternal lipoproteins,
allowing them to be transported across the placental barrier
mediated by plasma membrane fatty acid transporters
(FATP) and cytosolic fatty acid-binding proteins (FABP).
97
Although there is some controversy with respect to which
type of triglyceride hydrolase constitutes the major MVM
lipase activity, LPL and endothelial lipase (EL) are probably
the two key hydrolases.
96,97
The activity of placental LPL has
been reported to be increased in type-1 diabetes associated
with fetal overgrowth.
36
Furthermore, FABP1 protein
expression was upregulated in the placenta of both GDM and
type-1 diabetic women giving birth to large babies.
36
Lin-
degaard et al. reported increased placental mRNA expression
for EL and hormone-sensitive lipase, but not for LPL, in
type-1 diabetes associated with poor metabolic control and
fetal overgrowth.
98
Moreover, placental expression of
FABP4
99
and EL
100
is elevated in pregnancies of obese
women with GDM. These observations are consistent with an
increased placental capacity to supply lipids to the fetus in
Table 2. Placental transport in fetal overgrowth in association to
maternal diabetes
Transport system MVM BPM References
System A m,k2
86,87
System L m
a
,22
86,87
System b22
86
Lysine 22
86
Glucose 2m
b 88–90
Lipoprotein lipase mnd
36
Ca2
1
ATPase nd m
37
Na1/K
1
ATPase 22
91
MVM, microvillous plasma membrane; BPM, basal plasma
membrane; nd, not determined.
Transporter activity per mg of membrane protein was measured in
isolated MVM and BPM vesicles. The table shows the transport
activity in cases of fetal overgrowth in relation to gestational age
matched appropriately grown controls: increased (m), unaltered
(2) or reduced (k) transporter activity.
a
Only gestational diabetes.
b
Only type-1 diabetes.
106 F. Gaccioli et al.

maternal diabetes, however, considering the complexity of
placental lipid transport much more work is needed to draw
firm conclusions. In addition to the total amount, the FFA
composition of lipids made available to the fetus is of critical
importance for fetal development. Indeed, the content of
LCPUFAs in plasma phospholipids has been reported to be
decreased in fetuses of mothers with GDM,
101
implicating a
decreased supply of these fatty acids. Altogether, the data on
placental nutrient transport in pregnancies complicated by
diabetes is variable. However, the capacity to transport FFA
and, possibly, glucose may be increased in diabetic women, in
broad agreement with the placental nutrient sensing model.
The effect of maternal overweight and obesity on placental
function in women without diabetes remains largely
unknown.
102
More than half of all US women enter pregnancy
overweight or obese,
103
representing one of the most daunting
problem in obstetrical practice of today. It is well established that
high pre-pregnancy body mass index (BMI) is strongly asso-
ciated to fetal overgrowth.
104–106
Farley et al.
107
reported
decreased System A amino acid transport activity in placental
villous fragments isolated from placentas of obese Hispanic
women giving birth to normal sized babies. In contrast, pre-
liminary studies in our laboratory show that System A activity is
unaltered in MVM isolated from placentas of women with high
BMI in the same population.
108
Furthermore, our preliminary
data on Swedish women with varying pre-pregnancy BMI
indicate that System A, but not System L, amino acid transport
activity is increased in MVM isolated from placentas of obese
women giving birth to large babies.
109
Dube et al.
110
recently
reported increased placental LPL activity and gene and protein
expression of CD36 in obese mothers giving birth to normal
sized babies. On the other hand, placental expression of FATP4,
FABP1 and 3 was decreased in placentas of obese women.
110
However, protein expression studies and LPL activity measure-
ments in this study were done using placental homogenates,
which may not represent changes in syncytiotrophoblast plasma
membranes. Taken together, additional data is needed to allow
firm conclusions with respect to the impact of maternal obesity
on placental nutrient transport.
Studies in animal models
Reports on placental nutrient transport in animal models of
diabetes lack consistency. Diabetes in pregnancy has been
extensively studied in rodent models using surgical, chemical
and genetic approaches to induce the disease.
111
Of these
methods, administration of streptozotocin (STZ), which
selectively destroys pancreatic b-cells and reduces circulating
insulin resulting in hyperglycemia, has been widely employed
as a model of type-1 diabetes. However, at least in earlier
studies, this model was associated with severe maternal
hyperglycemia raising questions with respect to its relevance
to pregnant women with diabetes. Furthermore, utero-
placental blood flow has been reported to be reduced in rats
with STZ-induced diabetes
112,113
sometimes resulting in IUGR,
complicating the interpretation of placental nutrient transport
measurements in the context of increased maternal nutrient
availability. Nevertheless, placental transport capacity for neutral
amino acids has been shown to be decreased in STZ-treated
rats.
114
Placental expression of GLUT1 is downregulated
115
or
unchanged
116
in mice with STZ-induced diabetes, whereas
placental GLUT3 expression is increased in this model in
rats.
117
Transplacental glucose transport capacity in STZ rats
in vivo has been reported to be decreased, unchanged or
increased.
112,118,119
In addition, fatty acid transfer in STZ rats
has been shown to be increased or decreased.
120–122
It is likely
that the variable results on placental transport in STZ-treated
rodents are related to differences in the severity of metabolic
disturbance, variable effects on utero-placental blood flow and
differences in methodological approaches between studies.
The impact of maternal obesity on placental transport has
yet to be systematically described in well-characterized animal
models. The effect of a maternal high-fat diet and/or obesity
on fetal development has been explored extensively in a
variety of animal models.
123,124
However, the maternal
phenotype of these studies has received very little attention
and it is therefore not entirely clear to which extent these
models resemble obesity in pregnant women. Indeed, in
many of these paradigms fetal growth is restricted, which is
not the typical clinical outcome in humans.
104,105
One
explanation for the development of IUGR in animal models
of obesity is reduced utero-placental blood flow, which has
been reported for overnourished adolescent sheep
125
and in
chronically high-fat-fed non-human primates.
126
Over-
nutrition of the adolescent sheep is associated with an unal-
tered placental glucose transport capacity.
125
In adult obese
pregnant sheep provided 150% of the normal calorie intake,
fetal growth was enhanced at mid-gestation but fetal weight
was not different as compared with the controls close to
term.
7
Interestingly, there was a marked upregulation of
placental expression of FATP and increased fetal blood tri-
glycerides in this model, in particular at mid-gestation.
7
We explored a mouse model in which female mice were
given a high-fat diet (32%) for 8 weeks and subsequently
mated.
127
Dams continued their diet during pregnancy and
they were studied at GD 18.5. It was demonstrated that this
approach resulted in a modest increase in maternal adiposity
but not obesity, a metabolic profile resembling the obese
pregnant woman, without evidence of diabetes. Importantly,
this paradigm resulted in a fetal overgrowth and in vivo
transport studies demonstrated marked increases in placental
clearances of both
3
H-methyl-glucose and
14
C-MeAIB in
response to the high-fat diet. The increase in placental
clearance rates was associated with a significant increase in
GLUT1 and SNAT2 expression.
127
In a slightly different
approach, Rebholz et al.
128
fed female mice a diet containing
16% fat diet for 4 weeks and animals were subsequently
mated, which did not affect the adiposity or leptin levels of
the dam but resulted in increased fetal weights close to term
without affecting MVM GLUT1 expression. Collectively,
Maternal nutrition and placental transport 107

placental transport data from animal models of obesity is still
too scant to be applied to the fetal demand and placental
nutrient sensing models.
Mechanisms regulating placental transport in response
to changes in maternal nutrition
A detailed and full account of the mechanisms known to
regulate placental transport is beyond the scope of this
overview and the reader is referred to recent reviews.
18,129,130
Instead, we will briefly discuss factors reported to be altered in
response to changes in maternal nutrition and also shown to
regulate placental transport.
Under and overnutrition elicit changes in maternal metabo-
lism and levels of circulating hormones, which may regulate
placental function. Maternal protein restriction in the rat
3
and
calorie restriction in the mouse
67
are associated with decreased
maternal plasma insulin, insulin-growth factor (IGF)-I and
leptin. Furthermore, Sferruzzi-Perri et al.
67
demonstrated that a
20% restriction in total calorie intake in mice elevated maternal
corticosterone levels. Calorie restriction in non-pregnant humans
and animals typically increases serum concentrations of adipo-
nectin.
131
Maternal serum concentrations of IGF-I are decreased
in human IUGR
132
and some studies indicate that maternal
serum leptin concentrations are reduced in this pregnancy
complication.
133
In addition, placental insulin receptor num-
ber,
134
placental insulin/IGF-I signaling activity
135
and placental
leptin production
136
are reduced in IUGR. On the other
hand, maternal overnutrition appears to result in the opposite
hormonal changes. For example, obese pregnant women typi-
cally have higher serum levels of leptin, insulin, IGF-I and
interleukin-6 and decreased serum concentrations of adiponectin
as compared with pregnant women with normal pre-pregnancy
BMI
137,138
and similar changes are observed in GDM.
139
Furthermore, circulating maternal leptin was found to be
increased and adiponectin decreased in our pregnant mice fed
a high-fat diet,
127
consistent with obese pregnant women.
138
Thus, maternal undernutrition results in a catabolic hormo-
nal profile, whereas overnutrition causes changes in maternal
hormones that promote anabolism.
The significance of these changes in the levels of maternal
hormones and cytokines in response to nutrition is that these
factors have been shown to regulate placental nutrient transport.
For example, IGF-I,
140
insulin,
45,141
leptin
45
and cytokines
142
stimulate, whereas adiponectin inhibits trophoblast amino acid
transporter activity.
143
For IGF-I and adiponectin, these find-
ings have also been confirmed in vivo in the rodent.
144,145
Furthermore, administration of corticosteroids to pregnant
mice inhibits placental System A activity.
146
It is important to
note that receptors for many polypeptide hormones on the
syncytiotrophoblast cell, including receptors for insulin,
IGF-I and leptin,
147–149
are predominantly expressed in the
MVM, and therefore directly exposed to maternal blood.
Thus, it is likely that syncytiotrophoblast nutrient transporters
are mainly regulated by maternal rather than fetal hormones.
It is reasonable to assume that maternal under and over-
nutrition are associated with changes in placental nutrient,
oxygen and energy levels, which can regulate nutrient sensors
in the placenta. Signaling pathways involved in placental
nutrient sensing may include the amino acid response signal
transduction pathway, AMP-activated kinase, glycogen syn-
thase-3, the hexosamine signaling pathway and mammalian
target of rapamycin complex 1.
150
Of these nutrient sensors,
mTORC1 signaling may be of particular importance in
linking maternal nutrition to placental nutrient transport.
First, placental insulin/IGF-I signaling and fetal levels of
oxygen, glucose and amino acids are altered in pregnancy
complications such as IUGR,
41,50,135,151
and all these factors
are well-established upstream regulators of mTORC1.
152
Furthermore, mTORC1 is a positive regulator of placental
amino acid transporters,
153,154
suggesting that trophoblast
mTORC1 modulates amino acid transfer across the placenta.
In addition, placental mTORC1 signaling activity is changed
in pregnancy complications associated with altered fetal
growth and in animal models in which maternal nutrient
availability has been altered experimentally. For example,
placental mTORC1 activity is inhibited in human
IUGR
151,154
and preliminary studies indicate an activation of
placental mTORC1 signaling in association with maternal
obesity.
109,155
Furthermore, placental mTORC1 activity has
been reported to be decreased in hyperthermia-induced
IUGR in the sheep,
156
in response to a maternal low-protein
diet in the rat
8
and maternal calorie restriction in the
baboon.
59
Taken together, this evidence implicates mTORC1
signaling as an important placental nutrient sensor, which may
constitute a critical link between maternal nutrient availability
and fetal growth.
Placental signals originating from imprinted genes regulate
nutrient transport in the mouse placenta.
157
Imprinted genes
are predominantly expressed from one of two parental alleles
and in mice more than 70 imprinted genes have been dis-
covered. A subgroup of these genes are imprinted only in the
placenta and are involved in regulation of fetal and placental
growth.
157
An example of a paternally expressed/maternally
repressed placental gene is igf-2.
5
IGF-II regulates placental
growth and therefore indirectly its transport capacity. Inter-
estingly, Sferruzzi-Perri et al.
67
have provided evidence to
suggest that placental igf-2 plays a role in the placental
response to maternal undernutrition in mice.
67
Significant support for fetal demand signals regulating
placental amino acid transport comes from studies of mice
with placenta-specific knockout of igf-2. In this model, pla-
cental growth restriction occurs in mid-gestation and there is
a temporary upregulation of placental System A amino acid
transporter activity. This increased nutrient transport main-
tains fetal growth in the normal range until late pregnancy
when compensatory mechanisms fail and IUGR develops.
5,21
Based on a comparison of the placental phenotype in com-
plete igf-2 knockout mice and in mice with knockout of the
placental-specific igf-2 only, it has been suggested that fetal
108 F. Gaccioli et al.

IGF-II may be an important fetal demand signal.
158
However,
at least some studies in humans have shown that IGF-II levels
are reduced in IUGR fetuses
159
and higher in large-for-
gestational age fetuses,
160
which is not entirely consistent with
IGF-II as a fetal demand signal. In human pregnancy, it is
possible that fetal parathyroid hormone-related peptide regulates
the activity of the calcium pump in the syncytiotrophoblast
BPM.
37,161
Additional indirect evidence for fetal regulation of
placental transport functions comes from a study by Godfrey
et al.
162
showing that MVM System A amino acid transporter
activity is inversely correlated to fetal size within the normal
range of birth weights. Collectively, these observations are
consistent with the model proposing that placental nutrient
transporters are regulated by fetal demand; however, the nature
and identity of the fetal signals remain to be fully established.
Placental nutrient sensing and fetal demand: an
integrated model
In this review, we have focused on maternal, placental and
fetal signals that may regulate placental transport in response
to changes in maternal nutrition, which (when defined
broadly) also can include compromized utero-placental blood
flow. Because placental nutrient uptake/transport is inti-
mately related to the growth of the placenta, it is likely that
the signals that regulate nutrient uptake and transport in
the placenta also affect placental growth. Furthermore, by
releasing an array of hormones into the maternal circulation,
the placenta governs the maternal physiological adaptation to
pregnancy. It is therefore plausible that changes in placental
endocrine function in response to altered maternal nutrition
may regulate placental growth or transport functions indir-
ectly by affecting maternal physiology, adding an additional
level of complexity. In support of this concept, emerging
evidence shows that placental-specific deletion of igf-2
increases maternal corticosterone and insulin levels and
decreases plasma a-amino nitrogen.
67
We propose a model in which the placenta integrates a
multitude of maternal and fetal nutritional cues with infor-
mation from intrinsic nutrient-sensing signaling pathways
to balance fetal demand with the ability of the mother to
support the pregnancy by regulating maternal physiology,
placental growth and nutrient transport (Fig. 3). We argue
that these mechanisms have evolved due to the evolutionary
pressures of maternal undernutrition. Although these reg-
ulatory loops may function in the ‘reverse’ direction in
response to overnutrition, it is possible that these responses
may not be as readily apparent in maternal obesity or diabetes
as in response to maternal undernutrition. Fetal demand
signals are predicted to compensate for reduced nutrient
availability by upregulation of placental nutrient capacity,
which represents a homeostatic regulatory mechanism that is
a sound strategy from an evolutionary perspective. However,
the existence of maternal signals that in response to under-
nutrition will inhibit placental growth and nutrient transport
(placental nutrient sensing) is equally important from an
evolutionary point of view. Matching fetal growth to mater-
nal resources in response to maternal undernutrition will
Fig. 3. Placental nutrient sensing and fetal demand: an integrated model. We propose that the placenta integrates maternal and
fetal nutritional cues with information from intrinsic nutrient sensors, such as mammalian target of rapamycin (mTOR) signaling.
These signals then regulate placental growth and nutrient transport to balance fetal demand with the ability of the mother to support
pregnancy. Thus, the placenta plays a critical role in modulating maternal–fetal resource allocation, thereby affecting fetal growth and
the long-term health of the offspring. See text for detailed explanation. IGF-II, insulin-like growth factor II; PTHrp, parathyroid
hormone-related peptide.
Maternal nutrition and placental transport 109

produce an offspring that is smaller in size but who, in most
instances, will survive and be able to reproduce. This reduced
fetal growth is sometimes a better alternative than the fetus
extracting all the nutrients needed for normal growth from an
already deprived mother, thereby potentially jeopardizing
both maternal and fetal survival. We speculate that the rela-
tive importance of placental nutrient sensing and fetal
demand signals for the regulation of placental function may
differ between species and depend on the type, duration and
severity of the nutritional perturbation. For example, it is
plausible that regulation by fetal demand signals dominates
when the nutritional challenge is moderate and brief, whereas
regulation by placental nutrient sensing may override fetal
demand if the nutritional challenge is severe and prolonged.
Conclusion and future perspectives
Our long-term health is critically dependent on the avail-
ability of nutrients during fetal life, which is determined by
placental transport. The understanding of the role of the
placenta in fetal nutrition has evolved from the view that
the placenta constitutes a selective but passive filter to the
recognition that the placenta adapts to changes in maternal
nutrition by responding to maternal nutritional cues, fetal
demand signals and intrinsic nutrient-sensing signaling
pathways. The complexity of these regulatory pathways is
only beginning to be appreciated. A better understanding of
the molecular mechanisms regulating placental transport
functions may help to identify critical links between maternal
nutrition, fetal growth and developmental programming. In
addition, this knowledge is essential when designing novel
intervention strategies. However, currently our understanding
of these processes is limited, at best, presenting great chal-
lenges and opportunities for the future. For example, there is
a lack of information on the (1) molecular identity of fetal
demand signals, (2) the mechanisms by which lipids are
transported across the placenta and the role of placental lipid
transport in programming of obesity and diabetes, (3) how
multiple placental nutrient-sensing signaling pathways are
integrated and (4) how signals between the placenta and the
mother influence maternal–fetal resource allocation. Fur-
thermore, additional animal models that are relevant for the
human condition are needed, in particular for GDM and
maternal obesity. Finally, attention on the influence of fetal
sex, ethnicity, maternal age and parity on placental function is
required in future studies.
Acknowledgments
Figure 1 is reproduced by permission from Elsevier Ltd; this
figure was published in the chapter ‘Placental function and
materno-fetal exchange’ in Fetal Medicine: Basic Science and
Clinical Practice, 2 Ed, 2008, ISSN/ISBN 978-0-443-10408-
4. Supported by DK089989 (TLP), HD065007 (TJ and
TLP), HD068370 (TJ) and HD071306 (TJ).
References
1. Gluckman PD, Hanson MA, Cooper C, Thornburg KL.
Effect of in utero and early-life conditions on adult health and
disease. N Engl J Med. 2008; 359, 61–73.
2. Symonds ME, Sebert SP, Hyatt MA, Budge H. Nutritional
programming of the metabolic syndrome. Nat Rev Endocrinol.
2009; 5, 604–610.
3. Jansson N, Pettersson J, Haafiz A, et al. Down-regulation of
placental transport of amino acids precedes the development of
intrauterine growth restriction in rats fed a low protein diet.
J Physiol. 2006; 576, 935–946.
4. Malandro MS, Beveridge MJ, Kihlberg MS, Novak DA. Effect
of low-protein diet-induced intrauterine growth retardation on
rat placental amino acid transport. Am J Physiol. 1996; 271,
C295–C303.
5. Constancia M, Hemberger M, Hughes J, et al. Placental-
specific IGF-II is a major modulator of placental and fetal
growth. Nature. 2002; 417, 945–948.
6. Zhu MJ, Du M, Hess BW, Nathanielsz PW, Ford SP.
Periconceptional nutrient restriction in the ewe alters MAPK/
ERK1/2 and PI3K/Akt growth signaling pathways and
vascularity in the placentome. Placenta. 2007; 28, 1192–1199.
7. Zhu MJ, Ma Y, Long NM, Du M, Ford SP. Maternal obesity
markedly increases placental fatty acid transporter expression
and fetal blood triglycerides at midgestation in the ewe. Am J
Physiol Regul Integr Comp Physiol. 2010; 299, R1224–R1231.
8. Rosario FJ, Jansson N, Kanai Y, et al. Maternal protein
restriction in the rat inhibits placental insulin, mTOR, and
STAT3 signaling and down-regulates placental amino acid
transporters. Endocrinology. 2011; 152, 1119–1129.
9. Belkacemi L, Nelson DM, Desai M, Ross MG. Maternal
undernutrition influences placental-fetal development. Biol
Reprod. 2010; 83, 325–331.
10. Kaufmann P, Burton GJ. Anatomy and genesis of the placenta.
In The Physiology of Reproduction (eds. Knobil E, Neill JD)
1994; pp. 441–483. Raven Press: New York.
11. Kusinski LC, Jones CJ, Baker PN, Sibley CP, Glazier JD.
Isolation of plasma membrane vesicles from mouse placenta at
term and measurement of system A and system beta amino
acid transporter activity. Placenta. 2010; 31, 53–59.
12. Burton GJ, Kaufmann P, Huppertz B. Anatomy and genesis of
the placenta. In Knobil and Neill’s Physiology of Reproduction
(ed. Neill JD), 2006; pp. 189–241. Elsevier: Amsterdam.
13. Wooding FP, Flint APF. Placentation. In Marshall’s Physiology
of Reproduction (ed. Lamming GE) 1994; pp. 233–460.
Chapman & Hall: London.
14. Carter AM. Evolution of factors affecting placental oxygen
transfer. Placenta. 2009; 30(Suppl. A), S19–S25.
15. Jansson T, Powell TL. Placental function in maternofetal
exchange. In Fetal Medicine: Basic Science and Clinical Practice
(eds. Rodeck CH, Whittle MJ), 2009; pp. 97–109. Churchill
Livingstone Elsevier: London.
16. Sibley CP, Boyd RDH. Mechanisms of transfer across the
human placenta. In Fetal and Neonatal Physiology (eds. Polin
RA, Fox WW), 1998; pp. 77–89. WB Saunders Co.:
Philadelphia.
17. Sibley CP, Boyd RDH. Control of transfer across the mature
placenta. In Oxford Reviews of Reproductive Biology (ed. Clarke
JR), 1988; pp. 382–423. Oxford University Press: Oxford.
110 F. Gaccioli et al.

18. Atkinson DE, Boyd RDH, Sibley CP. Placental transfer.
In Knobil and Neill’s Physiology of Reproduction (ed. Neill JD)
2006; pp. 2787–2846. Elsevier: Amsterdam.
19. Jansson T, Powell TL. Human placental transport in altered
fetal growth: Does the placenta function as a nutrient sensor? –
A review. Placenta. 2006; 27(Suppl.), 91–97.
20. Sibley CP, Brownbill P, Dilworth M, Glazier JD. Review:
adaptation in placental nutrient supply to meet fetal growth
demand: implications for programming. Placenta. 2010;
31(Suppl.), S70–S74.
21. Constancia M, Angiolini E, Sandovici I, et al. Adaptation of
nutrient supply to fetal demand in the mouse involves
interaction between the Igf2 gene and placental transporter
systems. Proc Natl Acad Sci U S A. 2005; 102, 19219–19224.
22. Angiolini E, Coan PM, Sandovici I, et al. Developmental
adaptations to increased fetal nutrient demand in mouse
genetic models of Igf2-mediated overgrowth. FASEB J. 2011;
25, 1737–1745.
23. Lumey LH. Compensatory placental growth after restricted
maternal nutrition in early pregnancy. Placenta. 1998; 19,
105–111.
24. Sibley CP, Turner MA, Cetin I, et al. Placental phenotypes of
intrauterine growth. Pediatr Res. 2005; 58, 827–832.
25. Sibley C, D0Souza S, Glazier J, Greenwood S. Mechanisms of
solute transfer across the human placenta: effects of
intrauterine growth restriction. Fetal Matern Med Rev. 1998;
10, 197–206.
26. Cetin I, Alvino G. Intrauterine growth restriction: implications
for placental metabolism and transport. A review. Placenta.
2009; 30(Suppl. A), S77–S82.
27. Dicke JM, Verges DK. Neutral amino acid uptake by
microvillous and basal plasma membrane vesicles from
appropriate- and small-for- gestational age human pregnancies.
J Matern Fetal Med. 1994; 3, 246–250.
28. Jansson T, Ylve
´n K, Wennergren M, Powell TL. Glucose
transport and system A activity in syncytiotrophoblast
microvillous and basal membranes in intrauterine growth
restriction. Placenta. 2002; 23, 386–391.
29. Glazier JD, Cetin I, Perugino G, et al. Association between the
activity of the system a amino acid transporter in the
microvillous plasma membrane of the human placenta and
severity of fetal compromise in intrauterine growth restriction.
Pediatr Res. 1997; 42, 514–519.
30. Mahendran D, Donnai P, Glazier JD, et al. Amino acid
(System A) transporter activity in microvillous membrane
vesicles from the placentas of appropriate and small for
gestational age babies. Pediatr Res. 1993; 34, 661–665.
31. Jansson T, Scholtbach V, Powell TL. Placental transport of
leucine and lysine is reduced in intrauterine growth restriction.
Pediatr Res. 1998; 44, 532–537.
32. Norberg S, Powell TL, Jansson T. Intrauterine growth
restriction is associated with a reduced activity of placental
taurine transporters. Pediatr Res. 1998; 44, 233–238.
33. Roos S, Powell TL, Jansson T. Human placental taurine
transporter in uncomplicated and IUGR pregnancies: cellular
localization, protein expression, and regulation. Am J Physiol
Regul Integr Comp Physiol. 2004; 287, R886–R893.
34. Ayuk PTY, Theophanous D, D’Souza SW, Sibley CP, Glazier
JD. L-Arginine transport by the microvillous plasma
membrane of the syncytiotrophoblast from human placenta in
relation to nitric oxide production: effects of gestation,
preeclampsia, and intrauterine growth restriction. J Clin
Endocrinol Metab. 2002; 87, 747–751.
35. Jansson T, Wennergren M, Illsley NP. Glucose transporter
protein expression in human placenta throughout gestation
and in intrauterine growth retardation. J Clin Endocrinol
Metab. 1993; 77, 1554–1562.
36. Magnusson AL, Waterman IJ, Wennergren M, Jansson T,
Powell TL. Triglyceride hydrolase activities and expression of
fatty acid binding proteins in human placenta in pregnancies
complicated by IUGR and diabetes. J Clin Endocrinol Metab.
2004; 89, 4607–4614.
37. Strid H, Bucht E, Jansson T, Wennergren M, Powell T. ATP-
dependent Ca
21
transport across basal membrane of human
syncytiotrophoblast in pregnancies complicated by diabetes or
intrauterine growth restriction. Placenta. 2003; 24, 445–452.
38. Johansson M, Jansson T, Glazier JD, Powell TL. Activity and
expression of the Na
1
/H
1
exchanger is reduced in
syncytiotrophoblast microvillous plasma membranes isolated
from preterm intrauterine growth restriction pregnancies.
J Clin Endocrinol Metab. 2002; 87, 5686–5694.
39. Settle P, Sibley CP, Doughty IM, et al. Placental lactate
transporter activity and expression in intrauterine growth
restriction. J Soc Gynecol Investig. 2006; 13, 357–363.
40. Johansson M, Karlsson L, Wennergren M, Jansson T, Powell
TL. Activity and protein expression of Na
1
K
1
ATPase are
reduced in microvillous syncytiotrophoblast plasma
membranes isolated from pregnancies complicated by
intrauterine growth restriction. J Clin Endocrinol Metab. 2003;
88, 2831–2837.
41. Economides DL, Nicolaides KH. Blood glucose and oxygen
tension in small-for-gestational-age fetuses. Am J Obstet
Gynecol. 1989; 160, 120–126.
42. Zamudio S, Torricos T, Fik E, et al. Hypoglycemia and the
origin of hypoxia-induced reduction in human fetal growth.
PLoS One. 2010; 5, e8551.
43. Mackenzie B, Erickson JD. Sodium-coupled neutral amino
acid (System N/A) transporters of the SLC38 gene family.
Pflugers Arch. 2004; 447, 784–795.
44. Shibata E, Hubel CA, Powers RW, et al. Placental System A
amino acid transport is reduced in pregnancies complicated
with small for gestational age (SGA) infants but not in
preecalmpsia with SGA infants. Placenta. 2008; 29, 879–882.
45. Jansson N, Greenwood S, Johansson BR, Powell TL, Jansson
T. Leptin stimulates the activity of the system A amino acid
transporter in human placental villous fragments. J Clin
Endocrinol Metab. 2003; 88, 1205–1211.
46. von Versen-Hoynck F, Rajakumar A, Parrott MS, Powers RW.
Leptin affects system A amino acid transport activity in the
human placenta: evidence for STAT3 dependent mechanisms.
Placenta. 2009; 30, 361–367.
47. Tsitsiou E, Sibley CP, D’Souza SW, et al. Homocysteine is
transported by the microvillous plasma membrane of human
placenta. J Inherit Metab Dis. 2011; 34, 57–65.
48. Marconi AM, Paolini CL, Stramare L, et al. Steady
state maternal–fetal leucine enrichments in normal and
intrauterine growth-restricted pregnancies. Pediatr Res. 1999;
46, 114–119.
Maternal nutrition and placental transport 111

49. Paolini CL, Marconi AM, Ronzoni S, et al. Placental transport
of leucine, phenylalanine, glycine, and proline in intrauterine
growth-restricted pregnancies. J Clin Endocrinol Metab. 2001;
86, 5427–5432.
50. Cetin I, Corbetta C, Sereni LP, et al. Umbilical amino acid
concentrations in normal and growth-retarded fetuses sampled
in utero by cordocentesis. Am J Obstet Gynecol. 1990; 162,
253–261.
51. Cetin I, Marconi AM, Bozzetti P, et al. Umbilical amino acid
concentrations in appropriate and small for gestational age
infants: a biochemical difference present in utero. Am J Obstet
Gynecol. 1988; 158, 120–126.
52. Economides DL, Nicolaides KH, Gahl WA, Bernadini I,
Evans MI. Plasma amino acids in appropriate- and small-
for-gestational-age fetuses. Am J Obstet Gynecol. 1989; 161,
1219–1227.
53. Cetin I, Giovannini N, Alvino G, et al. Intrauterine growth
restriction is associated with changes in polyunsaturated fatty
acid fetal–maternal relationships. Pediatr Res. 2002; 52,
750–755.
54. Heasman L, Clarke L, Firth K, Stephenson T, Symonds ME.
Influence of restricted maternal nutrition in early to mid
gestation on placental and fetal development at term in sheep.
Pediatr Res. 1998; 44, 546–551.
55. Langley-Evans S, Gardner D, Jackson A. Association of
disproportionate growth of fetal rats in late gestation with
raised systolic blood pressure in later life. J Reprod Fertil. 1996;
106, 307–312.
56. Schlabritz-Loutsevitch N, Ballesteros B, Dudley C, et al.
Moderate maternal nutrient restriction, but not glucocorticoid
administration, leads to placental morphological changes in the
baboon (Papio sp). Placenta. 2007; 28, 783–793.
57. Dwyer CM, Madgwick AJ, Crook AR, Stickland NC. The
effect of maternal undernutrition on the growth and
development of the guinea pig placenta. J Dev Physiol. 1992;
18, 295–302.
58. Belkacemi L, Chen CH, Ross MG, Desai M. Increased
placental apoptosis in maternal food restricted gestations: role
of the Fas pathway. Placenta. 2009; 30, 739–751.
59. Kavitha JV, Nathanielsz PW, McDonald TJ, et al. Down
regulation of placental amino acid and glucose transporters in
response to maternal nutrient restriction in the baboon. Reprod
Sci. 2012; 19(Suppl.), 378A (Abstract).
60. Rosso P. Maternal-fetal exchange during protein malnutrition
in the rat. Placental transfer of glucose and a nonmetabolizable
glucose analog. J Nutr. 1977; 107, 20006–20010.
61. Rosso P. Maternal-fetal exchange during protein malnutrition
in the rat. Placental transfer of alpha-amino isobutyric acid.
J Nutr. 1977; 107, 2002–2005.
62. Rosso P. Maternal malnutrition and placental transfer of
alpha-aminoisobutyric acid in the rat. Science. 1975; 187,
648–650.
63. Varma DR, Ramakrishnan R. Effects of protein-calorie
malnutrition on transplacental kinetics of aminoisobutyric acid
in rats. Placenta. 1991; 12, 277–284.
64. Ahokas RA, Lahaye EB, Anderson GD, Lipshitz J. Effect of
maternal dietary restriction on fetal growth and placental
transfer of alpha-amino isobutyric acid in rats. J Nutr. 1981;
111, 2052–2058.
65. Belkacemi L, Jelks A, Chen CH, Ross MG, Desai M. Altered
placental development in undernourished rats: role of maternal
glucocorticoids. Reprod Biol Endocrinol. 2011; 9, 105.
66. Lesage J, Hahn D, Leonhardt M, et al. Maternal
undernutrition during late gestation-induced intrauterine
growth restriction in the rat is associated with impaired
placental GLUT3 expression, but does not correlate with
endogenous corticosterone levels. J Endocrinol. 2002; 174,
37–43.
67. Sferruzzi-Perri AN, Vaughan OR, Coan PM, et al. Placental-
specific Igf2 deficiency alters developmental adaptations to
undernutrition in mice. Endocrinology. 2011; 152, 3202–3212.
68. Coan PM, Vaughan OR, Sekita Y, et al. Adaptations in
placental phenotype support fetal growth during
undernutrition of pregnant mice. J Physiol. 2010; 588,
527–538.
69. Coan PM, Vaughan OR, McCarthy J, et al. Dietary
composition programmes placental phenotype in mice.
J Physiol. 2011; 589, 3659–3670.
70. Miller J, Turan S, Baschat AA. Fetal growth restriction. Semin
Perinatol. 2008; 32, 274–280.
71. Nitzan M, Orloff S, Schulman JD. Placental transfer of
analogs of glucose and amino acids in experimental
intrauterine growth retardation. Pediatr Res. 1979; 13,
100–103.
72. Glazier JD, Sibley CP, Carter AM. Effect of fetal growth
restriction on system A amino acid transporter activity in the
maternal facing plasma membrane of rat syncytiotrophoblast.
Pediatr Res. 1996; 40, 325–329.
73. Reid GJ, Lane RH, Flozak AS, Simmons RA. Placental
expression of glucose transporter proteins 1 and 3 in growth-
restricted fetal rats. Am J Obstet Gynecol. 1999; 180,
1017–1023.
74. Jansson T, Persson E. Placental transfer of glucose and
aminoacids in intrauterine growth retardation: studies with
substrate analogs in the awake guinea pig. Pediatr Res. 1990;
28, 203–208.
75. Saintonge J, Rosso P. Placental blood flow and transfer of
nutrient analogs in large, average, and small guinea pig
littermates. Pediatr Res. 1981; 15, 152–156.
76. Coan PM, Angiolini E, Sandovici I, et al. Adaptations in
placental nutrient transfer capacity to meet fetal growth
demands depend on placental size in mice. J Physiol. 2008;
586, 4567–4576.
77. Barry JS, Rozance PJ, Anthony RV. An animal model of
placental insufficiency-induced intrauterine growth restriction.
Semin Perinatol. 2008; 32, 225–230.
78. Thureen PJ, Trembler KA, Meschia G, Makowski EL,
Wilkening RB. Placental glucose transport in heat-induced
fetal growth retardation. Am J Physiol. 1992; 263,
R578–R585.
79. Ross JC, Fennessey PV, Wilkening RB, Battaglia FC, Meschia
G. Placental transport and fetal utilization of leucine in a
model of fetal growth retardation. Am J Physiol. 1996; 270,
E491–E503.
80. Anderson AH, Fennessey PV, Meschia G, Wilkening RB,
Battaglia FC. Placental transport of threonine and its
utilization in the normal and growth-restricted fetus.
Am J Physiol. 1997; 272, E892–E900.
112 F. Gaccioli et al.

81. de Vrijer B, Regnault TR, Wilkening RB, Meschia G,
Battaglia FC. Placental uptake and transport of ACP, a neutral
nonmetabolizable amino acid, in an ovine model of fetal
growth restriction. Am J Physiol. 2004; 287, E1114–E1124.
82. Crowe C, Dandekar P, Fox M, et al. The effects of anaemia on
heart, placenta and body weight, and blood pressure in fetal
and neonatal rats. J Physiol. 1995; 488, 515–519.
83. Godfrey KM, Barker DJ. Maternal nutrition in relation to fetal
and placental growth. Eur J Obstet Gynecol Reprod Biol. 1995;
61, 15–22.
84. Gambling L, Danzeisen R, Gair S, et al. Effect of iron
deficiency on placental transfer of iron and expression of iron
transport proteins in vivo and in vitro. Biochem J. 2001; 356,
883–889.
85. Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and
adverse pregnancy outcomes. N Engl J Med. 2008; 358,
1991–2002.
86. Jansson T, Ekstrand Y, Bjo
¨rn C, Wennergren M, Powell TL.
Alterations in the activity of placental amino acid transporters
in pregnancies complicated by diabetes. Diabetes. 2002; 51,
2214–2219.
87. Kuruvilla AG, D’Souza SW, Glazier JD, et al. Altered activity
of the system A amino acid transporter in microvillous
membrane vesicles from placentas of macrosomic babies born
to diabetic women. J Clin Invest. 1994; 94, 689–695.
88. Jansson T, Ekstrand Y, Wennergren M, Powell TL. Placental
glucose transport in gestational diabetes. Am J Obstet Gynecol.
2001; 184, 111–116.
89. Jansson T, Wennergren M, Powell TL. Placental glucose
transport and GLUT 1 expression in insulin dependent
diabetes. Am J Obstet Gynecol. 1999; 180, 163–168.
90. Gaither K, Quraishi AN, Illsley NP. Diabetes alters the
expression and activity of the human placental GLUT1 glucose
transporter. J Clin Endocrinol Metab. 1999; 84, 695–701.
91. Persson A, Johansson M, Jansson T, Powell TL. Na
1
/K
1
-
ATPase activity and expression in syncytiotrophoblast plasma
membranes in pregnancies complicated by diabetes. Placenta.
2002; 23, 386–391.
92. Dicke JM, Henderson GI. Placental amino acid uptake in
normal and complicated pregnancies. Am J Med Sci. 1988;
295, 223–227.
93. Bibee KP, Illsley NP, Moley KH. Asymmetric syncytial
expression of GLUT9 splice variants in human term placenta
and alterations in diabetic pregnancies. Reprod Sci. 2011; 18,
20–27.
94. Osmond DT, Nolan CJ, King RG, Brennecke SP, Gude NM.
Effects of gestational diabetes on human placental glucose
uptake, transfer, and utilisation. Diabetologia. 2000; 43,
576–582.
95. Osmond DT, King RG, Brennecke SP, Gude NM. Placental
glucose transport and utilisation is altered at term in insulin-
treated, gestational-diabetic patients. Diabetologia. 2001; 44,
1133–1139.
96. Desoye G, Gauster M, Wadsack C. Placental transport in
pregnancy pathologies. Am J Clin Nutr. 2011; 94(Suppl 6),
1896S–1902S.
97. Gil-Sanchez A, Koletzko B, Larque E. Current understanding
of placental fatty acid transport. Curr Opin Clin Nutr Metab
Care. 2012; 15, 265–272.
98. Lindegaard MLS, Damm P, Mathiesen ER, Nielsen LB.
Placental triglyceride accumulation in maternal type 1 diabetes
is associated with increased lipase gene expression. J Lipid Res.
2006; 47, 2581–2588.
99. Scifres CM, Chen B, Nelson DM, Sadovsky Y. Fatty acid
binding protein 4 regulates intracellular lipid accumulation in
human trophoblasts. J Clin Endocrinol Metab. 2011; 96,
E1083–E1091.
100. Gauster M, Hiden U, van Poppel M, et al. Dysregulation of
placental endothelial lipase in obese women with gestational
diabetes mellitus. Diabetes. 2011; 60, 2457–2464.
101. Wijendran V, Bendel RB, Couch SC, et al. Fetal erythrocyte
phospholipid polyunsaturated fatty acids are altered in
pregnancy complicated with gestational diabetes mellitus.
Lipids. 2000; 35, 927–931.
102. Higgins L, Greenwood SL, Wareing M, Sibley CP, Mills TA.
Obesity and the placenta: a consideration of nutrient exchange
mechanisms in relation to aberrant fetal growth. Placenta.
2011; 32, 1–7.
103. Chu SY, Kim SY, Bish CL. Prepregnancy obesity prevalence in
the United States, 2004–2005. Matern Child Health J. 2009;
13, 614–620.
104. Sebire NJ, Jolly M, Harris JP, et al. Maternal obesity and
pregnancy outcome: a study of 287,213 pregnancies in
London. Int J Obes Relat Metab Disord. 2001; 25, 1175–1182.
105. Baeten JM, Bukusi EA, Lambe M. Pregnancy complications
and outcomes among overweight and obese nulliparous
women. Am J Publ Health. 2001; 91, 436–440.
106. Ehrenberg HM, Mercer BM, Catalano PM. The influence of
obesity and diabetes on the prevalence of macrosomia. Am J
Obstet Gynecol. 2004; 191, 964–968.
107. Farley DM, Choi J, Dudley DJ, et al. Placental amino acid
transport and placental leptin resistance in pregnancies
complicated by maternal obesity. Placenta. 2010; 31, 718–724.
108. Gaccioli F, Jansson T, Powell TL. Placental System A and
System L amino acid transporter activity and expression in lean
and overweight/obese Hispanic women. Reprod Sci. 2012; 19,
377A (Abstract).
109. Jansson N, Jones HN, Schumacher M, et al. Altered AMPK
and mTOR signaling and up-regulation of placental System A
amino acid transporter activity and SNAT2 protein expression
in obese women giving birth to large babies. Reprod Sci. 2010;
17, 260A (Abstract).
110. Dube E, Gravel A, Martin C, et al. Modulation of fatty acid
transport and metabolism by obesity in the human full-term
placenta. Biol Reprod. 2012; May 2 [E-pub ahead of print].
111. Jawerbaum A, White V. Animal models in diabetes and
pregnancy. Endocr Rev. 2010; 31, 680–701.
112. Palacin M, Lasuncion MA, Martin A, Herrera E. Decreased
uterine blood flow in the diabetic pregnant rat does not modify
the augmented glucose transfer to the fetus. Biol Neonate.
1985; 48, 197–203.
113. Eriksson U, Jansson L. Diabetes in pregnancy: decreased
placental blood flow and disturbed fetal development in the
rat. Pediatr Res. 1984; 18, 735–738.
114. Copeland AD Jr, Porterfield SP. Effects of streptozotocin-
induced diabetes in pregnant rats on placental transport and
tissue uptake of alpha-amino-isobutyric acid. Horm Metab Res.
1987; 19, 57–61.
Maternal nutrition and placental transport 113

115. Ogura K, Sakata M, Yamaguchi M, Kurachi H, Murata Y.
High concentration of glucose decreases glucose transporter-1
expression in mouse placenta in vitro and in vivo. J Endocrinol.
1999; 160, 443–452.
116. Devaskar S, Devaskar U, Schroeder R, et al. Expression of
genes involved in placental glucose uptake and transport in the
nonobese diabetic mouse pregnancy. Am J Obstet Gynecol.
1994; 171, 1316–1323.
117. Boileau P, Mrejen C, Girard J, Hauguel-de-Mouzon S.
Overexpression of GLUT 3 placental glucose transporter in
diabetic rats. J Clin Invest. 1995; 96, 309–317.
118. Herrera E, Palacin M, Martin A, Lasuncion M. Relationship
between maternal and fetal fuels and placental glucose transfer
in rats with maternal diabetes of varying severity. Diabetes.
1985; 34(Suppl 2), 42–46.
119. Thomas C, Lowy C. Placental transfer and uptake of
2-deoxyglucose in control and diabetic rats. Metabolism.
1992; 41, 1199–1203.
120. Honda M, Lowy C, Thomas CR. The effects of maternal
diabetes on placental transfer of essential and non-essential
fatty acids in the rat. Diabetes Res. 1990; 15, 47–51.
121. Shafrir E, Khassis S. Maternal-fetal fat transport versus new fat
synthesis in the pregnant diabetic rat. Diabetologia. 1982; 22,
111–117.
122. Goldstein R, Levy E, Shafrir E. Increased maternal-fetal
transport of fat in diabetes assessed by polyunsaturated fatty
acid content in fetal lipids. Biol Neonate. 1985; 47, 343–349.
123. Li M, Sloboda DM, Vickers MH. Maternal obesity and
developmental programming of metabolic disorders in
offspring: evidence from animal models. Exp Diabetes Res.
2011; 2011, 592408. Epub 28 September 2011.
124. Armitage JA, Khan IY, Taylor PD, Nathanielsz PW, Poston L.
Developmental programming of metabolic syndrome by
maternal nutritional imbalance; how strong is the evidence from
expermental models in animals. JPhysiol. 2004; 561, 355–377.
125. Wallace JM, Bourke DA, Aitken RP, Milne JS, Hay WW Jr.
Placental glucose transport in growth-restricted pregnancies
induced by adolescent sheep. J Physiol. 2003; 547, 85–94.
126. Frias AE, Morgan TK, Evans AE, et al. Maternal high-fat diet
disturbs uteroplacental hemodynamics and increases the
frequency of stillbirth in a nonhuman primate model of excess
nutrition. Endocrinology. 2011; 152, 2456–2464.
127. Jones HN, Woollett LP, Barbour N, et al. High fat diet before
and during pregnancy causes marked up-regulation of
placental nutrient transport and fetal overgrowth in C57/Bl6
mice. FASEB J. 2009; 23, 271–278.
128. Rebholz SL, Burke KT, Yang Q, Tso P, Woollett LA. Dietary
fat impacts fetal growth and metabolism: uptake of
chylomicron remnant core lipids by the placenta. Am J Physiol
Endocrinol Metab. 2011; 301, E416–E425.
129. Jones HN, Powell TL, Jansson T. Regulation of placental
nutrient transport – a review. Placenta. 2007; 28, 763–774.
130. Lager S, Powell TL. Regulation of transport across the
placenta. J Pregnancy. 2012 (In Press).
131. Longo VD, Fontana L. Calorie restriction and cancer
prevention: metabolic and molecular mechanisms. Trends
Pharmacol Sci. 2010; 31, 89–98.
132. Holmes R, Montemagno R, Jones J, et al. Fetal and maternal
plasma insulin-like growth factors in pregnancies with
appropriate or retarded fetal growth. Early Hum Dev. 1997;
49, 7–17.
133. Yildiz L, Avci B, Ingec M. Umbilical cord and maternal blood
leptin concentrations in intrauterine growth retardation. Clin
Chem Lab Med. 2002; 40, 1114–1117.
134. Potau N, Riudor E, Ballabriga A. Insulin receptors in
human placenta in relation to fetal weight and gestational age.
Pediatr Res. 1981; 15, 798–802.
135. Laviola L, Perrini S, Belsanti G, et al. Intrauterine growth
restriction in humans is associated with abnormalities in
placental insulin-like growth factor signaling. Endocrinology.
2005; 146, 1498–1505.
136. Lea RG, Howe D, Hannah LT, et al. Placental leptin in
normal diabetic and fetal growth-retarded pregnancies. Mol
Hum Reprod. 2000; 6, 763–769.
137. Ramsay JE, Ferrell WR, Crawford L, et al. Maternal obesity is
associated with dysregulation of metabolic, vascular and
inflammatory pathways. J Clin Endocrinol Metab. 2002; 87,
4231–4237.
138. Jansson N, Nilsfelt A, Gellerstedt M, et al. Maternal hormones
linking maternal bodymass index and dietary intake to birth
weight. Am J Clin Nutr. 2008; 87, 1743–1749.
139. Lauszus FF, Klebe JG, Flyvbjerg A. Macrosomia associated
with maternal serum insulin-like growth factor-I and -II in
diabetic pregnancy. Obstet Gynecol. 2001; 97, 734–741.
140. Karl PI. Insulin-like growth factor-1 stimulates amino acid
uptake by the cultured human placental trophoblast. J Cell
Physiol. 1995; 165, 83–88.
141. Karl PI, Alpy KL, Fischer SE. Amino acid transport by the
cultured human placental trophoblast: effect of insulin on AIB
transport. Am J Physiol. 1992; 262, C834–C839.
142. Jones HN, Jansson T, Powell TL. IL-6 stimulates System A
amino acid transporter activity in trophoblast cells through
STAT3 and increased expression of SNAT2. Am J Physiol Cell.
2009; 297, C1228–C1235.
143. Jones HN, Jansson T, Powell TL. Full length adiponectin
attenuates insulin signaling and inhibits insulin-stimulated
amino acid transport in human primary trophoblast cells.
Diabetes. 2010; 59, 1161–1170.
144. Rosario FJ, Schumacher MA, Jiang J, et al. Chronic maternal
infusion of full-length adiponectin in pregnant mice down-
regulates placental amino acid transporter activity and expression
and decreases fetal growth. JPhysiol. 2012; 590, 1495–1509.
145. Sferruzzi-Perri AN, Owens JA, Standen P, et al. Early
treatment of the pregnant guinea pig with IGFs promotes
placental transport and nutrition partitioning near term.
Am J Physiol Endocrinol Metab. 2006; 292, E668–E676.
146. Audette MC, Challis JR, Jones RL, Sibley CP, Matthews SG.
Antenatal dexamethasone treatment in midgestation reduces
system A-mediated transport in the late-gestation murine
placenta. Endocrinology. 2011; 152, 3561–3570.
147. Desoye G, Hartmann M, Blaschitz A, et al. Insulin receptors in
syncytiotrophoblast and fetal endothelium of human placenta.
Immunohistochemical evidence for developmental changes in
distribution pattern. Histochemistry. 1994; 101, 277–285.
148. Ebenbichler CF, Kasser S, Laimer M, et al. Polar expression
and phosphorylation of human leptin receptor isoforms in
paired syncytial, microvillous and basal membranes from
human term placenta. Placenta. 2002; 23, 516–521.
114 F. Gaccioli et al.

149. Fang J, Furesz TC, Lurent RS, Smith CH, Fant M. Spatial
polarization of insulin-like growth factor receptors on the
human syncytiotrophoblast. Pediatr Res. 1997; 41, 258–265.
150. Jansson T, Aye ILMH, Goberdhan DCI. The emerging role of
mTORC1 signalling in placental nutrient-sensing. Placenta.
2012 June 9. [Epub ahead of print].
151. Yung HW, Calabrese S, Hynx D, et al. Evidence of translation
inhibition and endoplasmic reticulum stress in the etiology of
human intrauterine growth restriction. Am J Pathol. 2008;
173, 311–314.
152. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal
integration to cancer, diabetes and ageing. Nat Rev Mol Cell
Biol. 2011; 12, 21–35.
153. Roos S, Kanai Y, Prasad PD, Powell TL, Jansson T.
Regulation of placental amino acid transporter activity by
mammalian target of rapamycin. Am J Physiol Cell. 2009; 296,
C142–C150.
154. Roos S, Jansson N, Palmberg I, et al. Mammalian target of
rapamycin in the human placenta regulates leucine transport
and is down-regulated in restricted foetal growth. J Physiol.
2007; 582, 449–459.
155. Gaccioli F, Jansson T, Powell TL. Activation of placental
mammalian target of rapamycin signaling in obese women.
Placenta. 2011; 32, A134 Abstract.
156. Arroyo JA, Brown LD, Galan HL. Placental mammalian target
of rapamycin and related signaling pathways in an ovine model
of intrauterine growth restriction. Am J Obstet Gynecol. 2009;
201, 616e611–616e617.
157. Coan PM, Burton GJ, Ferguson-Smith AC. Imprinted genes
in the placenta – a review. Placenta. 2005; 26(Suppl. A),
S10–S20.
158. Coan PM, Fowden AL, Constancia M, et al. Disproportional
effects of Igf2 knockout on placental morphology and
diffusional exchange characteristics in the mouse. J Physiol.
2008; 586, 5023–5032.
159. Smerieri A, Petraroli M, Ziveri MA, et al. Effects of cord
serum insulin, IGF-II, IGFBP-2, IL-6 and cortisol
concentrations on human birth weight and length: pilot study.
PLoS One. 2011; 6, e29562.
160. Christou H, Connors JM, Ziotopoulou M, et al. Cord blood
leptin and insulin-like growth factor levels are independent
predictors of fetal growth. J Clin Endocrinol Metab. 2001; 86,
935–938.
161. Strid H, Care AD, Jansson T, Powell TL. PTHrp
midmolecule stimulates Ca
21
ATPase in human
syncytiotrophoblast basal membrane. J Endocrinol. 2002; 175,
517–524.
162. Godfrey KM, Matthews N, Glazier J, et al. Neutral amino
acid uptake by microvillous plasma membrane of the
human placenta is inversely related to fetal size at birth in
normal pregnancy. J Clin Endocrinol Metab. 1998; 83,
3320–3326.
Maternal nutrition and placental transport 115