altered fetal growth represents an important risk factor for complications in the perinatal period [ 1 , 2 ] and is associated with the development of cardiovascular disease , obesity , and diabetes in adult life [ 37 ] . fetal growth is largely determined by nutrient supply , which is dependent upon placental nutrient transport . in human pregnancies complicated by either intrauterine growth restriction ( iugr ) or fetal overgrowth information on molecular mechanisms regulating placental nutrient transporters is critical for understanding the development of pregnancy complications , as well as how maternal nutrition and metabolic disturbances affect fetal growth . furthermore , the placenta with its nutrient transport functions is increasingly seen as being the mediator of maternal nutrition effects on the lifelong health consequences for the child [ 810 ] . several factors influence transport across the placenta : uteroplacental and umbilical blood flows , area available for exchange , placental metabolism , and activity / expression of specific transporter proteins in the placental barrier . transfer of highly permeable molecules such as oxygen and carbon dioxide is particularly influenced by reduced blood flow . for less permeable substrates the placenta possesses both passive and active transport mechanisms . other nutrients ( e.g. , calcium ) are transported by primary active transport ; a process directly linked to the hydrolysis of adenosine triphosphate . a wide range of nutrients ( e.g. , amino acids , phosphorus , and lactate ) are transported across the placenta mediated by secondary active transport , utilizing energy provided by ion gradients such as sodium , chloride , and protons [ 1416 ] . changes in energy availability or ion gradients can profoundly influence net transfer of substrates transported by active mechanisms . in this paper , we will focus on circulating and placental factors as well as placental signaling pathways regulating key placental macronutrient transporters . the primary barrier limiting nutrient transfer across the human placenta is the syncytiotrophoblast [ 9 , 17 ] . the syncytiotrophoblast has two polarized plasma membranes : a maternal - facing microvillous plasma membrane ( mvm ) and a basal plasma membrane ( bm ) oriented towards the fetal circulation ( figure 1 ) . transport characteristics of these two plasma membranes will have a major influence on net placental nutrient transport and consequently fetal growth . the syncytiotrophoblast plasma membranes express numerous nutrient transporters which may be regulated by fetal , maternal , and placental signals ( figure 2 ) . significant support for fetal demand signals regulating placental amino acid transport comes from studies of mice with placenta specific knockout of the insulin - like growth factor 2 gene ( igf2 ) . placental growth restriction occurs in midgestation and system a amino acid transporter activity is initially upregulated in this model . the increased nutrient transport maintains fetal growth within the normal range until late pregnancy when compensatory mechanisms fail and iugr develops [ 18 , 19 ] . at least some studies in humans have shown that igf - ii levels are reduced in iugr fetuses   and higher in large for gestational age ( lga ) fetuses . the finding that mvm system a amino acid transporter activity is inversely correlated to fetal size within the normal range of birth weights provides indirect evidence for fetal regulation of placental transport functions . in human pregnancy , studies suggest that fetal parathyroid hormone - related peptide ( pthrp ) regulates activity of the calcium pump in the bm [ 23 , 24 ] . placental signals originating from imprinted genes have been shown to regulate nutrient transport in the mouse placenta . imprinted genes are predominantly expressed from one of two parental alleles , and in mice approximately 70 imprinted genes have been discovered . a subgroup of these genes are imprinted only in the placenta and are involved in regulation of fetal and placental growth . interestingly , system a or sodium - dependent neutral amino acid transporter ( snat ) isoform 4 ( encoded by slc38a4 ) is expressed from the paternal allele in mouse placenta [ 25 , 26 ] . thus , the paternal genome may exert influence on placental amino acid transport capacity and fetal growth by means of paternally imprinted placental genes . in addition to imprinted genes , numerous placental signaling pathways , such as mammalian target of rapamycin ( mtor ) , regulate nutrient transporters . furthermore a wide array of cytokines , hormones , and signaling molecules are synthesized and secreted by the placenta and could affect its nutrient transporters in an autocrine / paracrine fashion . there is strong support for regulation of placental nutrient transport by maternal factors , particularly by metabolic hormones . the mvm of the syncytiotrophoblast expresses numerous hormone receptors , including receptors for insulin [ 27 , 28 ] , igf - i , and leptin , consistent with regulation of trophoblast function by maternal hormones . in subsequent sections , we will review circulating factors , placental factors , and placental signaling pathways known to regulate placental transporters for amino acids , fatty acids , and glucose . we will also discuss changes in activity and expression of placental nutrient transporters in pregnancies complicated by abnormal fetal growth . the primary focus will be on data obtained from studies of human placenta ; animal studies will be discussed as appropriate , primarily when human data is lacking . amino acid uptake across cellular membranes is mediated through active transporter processes ; these mechanisms can be separated into accumulative transporters and exchangers . the accumulative transporters increase intracellular amino acid concentrations by mediating uptake against their concentration gradient , usually by cotransporting extracellular sodium . exchangers alter the intracellular amino acid composition by exchanging amino acids between the intracellular and extracellular compartments [ 31 , 32 ] . amino acid transporters can be further categorized into distinct systems depending on characteristics such as substrate specificity and sodium dependence . the human placenta expresses more than 20 different amino acid transporters [ 14 , 33 ] . fetal amino acid concentrations are generally higher than maternal levels , reflecting an active transport mechanism across the placenta . efflux of amino acids across the bm has been suggested to be dependent on amino acid exchangers together with facilitative efflux transporters . the system a amino acid transporter facilitates uptake of small non - essential neutral amino acids such as alanine , glycine , and serine . this transporter system enables uptake of amino acids against their concentration gradient by simultaneously transporting sodium into the cell . system a activity has been measured in both plasma membranes of the syncytiotrophoblast , however , highly polarized to the mvm . importantly , system a activity contributes to the high intracellular concentration of amino acids such as glycine , which are exchanged for extracellular essential amino acids via system l ( see the following ) . system a activity is thus important for placental transport of both non - essential and essential amino acids . human first and third trimester placenta express three isoforms of system a : snat1 ( slc38a1 ) , snat2 ( slc38a2 ) , and snat4 ( slc38a4 ) . during pregnancy the relative contributions of the three isoforms to total system desforges et al . have provided evidence suggesting that the snat4 contribution is higher in first trimester compared to term placenta . additionally , snat1 is the major contributor to system a activity in cultured primary trophoblast cells from term placentas . system a activity has been reported to increase with advancing gestation [ 36 , 38 ] , but conflicting results have been reported . placental system a transporter activity is reduced in human pregnancies complicated by iugr [ 35 , 40 ] . however , it is unclear whether reduced amino acid transport occurs prior to fetal growth restriction or as a consequence of decreased fetal needs . in animal studies of growth restriction , reduction in system a activity has been shown to precede impaired fetal growth [ 41 , 42 ] . these studies suggest alterations in system a transporters may be contributing to the development of iugr . insulin [ 4346 ] , interleukin ( il)-6 , and tumor necrosis factor ( tnf)-   stimulate activity of this transporter . importantly , the stimulatory effect of insulin , il-6 , and tnf- occurs at concentrations within the physiological range . the mechanism through which tnf- stimulates system a is unknown , but the effect of il-6 is dependent on signal transducer and activator of transcription ( stat)3 . the involvement of stat3 in regulating placental amino acid transport has also been demonstrated in villous fragments where stat3 is required for stimulation of system a activity by leptin . preliminary studies show oleic acid activates stat3 ; this fatty acid also increases system a activity through a toll - like receptor-4 dependent mechanism in cultured trophoblast cells . another placental signaling pathway regulating placental system a activity is mtor , which we have suggested functions as an integrator of maternal , fetal , and placental signaling molecules ( e.g. , hormones , growth factors , and nutrient levels ) . mtor is an important regulator of growth for individual cells as well as whole organs . in placenta from pregnancies complicated by iugr , obese women have an increased risk of delivering large babies , and placental mtor activity increases in such pregnancies . in cultured trophoblast cells , mtor functions as a positive regulator of system a activity [ 46 , 54 ] without affecting global expression of the three snat isoforms , but rather at the posttranslational level by affecting plasma membrane trafficking of the snat2 isoform .  
 in utero exposure to glucocorticoids is associated with reduced fetal growth , and glucocorticoids affect placental system a activity . dexamethasone ( a synthetic glucocorticoid ) stimulates system a activity in cultured primary trophoblast cells   and in explants from term placenta . this stimulatory effect may depend upon cortisol 's ability to increase snat2 expression   because a 1-hour exposure does not alter system a activity in placental villous explants . notably , dexamethasone administered to pregnant mice downregulates placental system a amino acid transport   suggesting the effects of glucocorticoids on system a activity in vitro and in vivo are distinct . leptin stimulates placental system a activity [ 43 , 45 ] , yet the effect appears limited to acute stimulation because longer exposures did not alter amino acid uptake [ 45 , 61 ] . contrarily , the stimulatory effect of insulin is more robust , since insulin stimulates system a activity after both acute and longer exposures [ 4346 ] . insulin 's stimulatory effect on system a activity is inhibited by full - length adiponectin . in contrast to other tissues , this implies adiponectin causes placental insulin resistance rather than promoting increased insulin sensitivity . the form of adiponectin is also important since globular adiponectin increases system a activity , while full - length adiponectin alone does not . interestingly , infusing pregnant mice with full - length adiponectin results in reduced placental system a activity and restricted fetal growth . although it has been suggested that the insulin receptor is expressed primarily in endothelial cells of fetal capillaries at term , recent evidence suggests otherwise . igf - i stimulates system a activity and can initiate signaling through both igf - i and insulin receptors [ 46 , 78 ] . in a two - sided model , bloxam et al . demonstrated trophoblast cells exposed to igf - i on the apical side increased intracellular accumulation of aib ( a system a substrate ) but also reduced overall transfer rate . although mvm uptake is the first step in transferring nutrients across the placenta , this finding highlights that increased uptake may not always result in an increased net transport . other factors are reported to reduce placental system a activity , including hypoxia   and il-1 . in explants from term placenta , acute but not chronic exposure to angiotensin ii reduced activity of the system a transporter . blocking the sodium pump with ouabain or subjecting villous explants to a chronic exposure to urocortin and corticotropin - releasing hormone ( crh ) also cause reduction in system a activity . while most studies are performed with term placenta tissue , first or second trimester placenta may respond differently to stimuli . for example , growth hormone ( gh ) reduced system a activity in villous tissue from first trimester , but not those from term placenta . conversely , insulin has no effect in early pregnancy while it stimulates activity of system a transporter in third trimester [ 39 , 43 ] . the system l transporter is a sodium - independent obligatory exchanger of neutral amino acids . non - essential amino acids are exchanged for predominantly essential amino acids , with either aromatic or branched side chains ( e.g. , leucine and phenylalanine ) enabling transport against their concentration gradient . the system l transporter consists of a heterodimer formed from a light chain protein : large neutral amino acid transporter ( lat)1 ( slc7a5 ) or lat2 ( slc7a8 ) together with a heavy chain transmembrane protein : 4f2hc / cd98 ( slc3a2 ) [ 32 , 101 ] . expression of 4f2hc and lat1 is higher in term placenta compared to midgestation placenta . cellular localization of the lat isoforms is polarized , with lat1 primarily found in the mvm and lat2 in the bm [ 101103 ] . although bm may be the primary localization of lat2 , it is not exclusively expressed in this plasma membrane since functional activity of lat2 has been demonstrated in isolated mvm vesicles . the bm localization of lat2 allows for exchange of amino acids between non - essential amino acids in the fetal compartment with essential amino acids in the cytoplasm . the bm also expresses the efflux transporters tat1 ( slc16a10 ) , lat3 ( slc43a1 ) , and lat4 ( slc43a2 ) ; these transporters may play an important role in the net efflux of amino acids to the fetus . similar to the system a transporter , activity of the system l transporter has been reported in both plasma membranes of the syncytiotrophoblast , although with higher activity measured in the mvm . the activity of system l in the mvm decreases in cases of reduced fetal growth , both in human   and animal models [ 42 , 62 ] .   in cultured primary trophoblast cells system l amino acid transporter activity is not affected by factors known to regulate system a activity ( e.g. , il-6 , tnf- , or adiponectin ) . yet , in a pregnant mouse model , a four - day infusion of full - length adiponectin caused reduced fetal growth and downregulation of system l activity as well as expression of the two lat isoforms . conflicting results have been reported for insulin regulation of system l activity . in one study , insulin modestly increased system l activity in cultured primary trophoblast cells , whereas no effect was observed in another study using similar approaches .   studies of cultured trophoblast cells   and villous explants   from term placenta have demonstrated that the mtor signaling pathway functions as a positive regulator of placental system l activity . exposing trophoblast cells to rapamycin , an mtor inhibitor , reduces system l activity [ 50 , 54 ] and decreases lat1 mrna expression . furthermore , mtor inhibition prevented the increase in leucine uptake observed after incubation of primary human trophoblast cells in insulin or glucose . activation of protein kinase c together with increased intracellular calcium levels in bewo cells increases expression of 4f2hc and lat1 and stimulates system l activity . cocaine and nicotine use during pregnancy are associated with lower birth weights , resulting in studies exploring the effects of such drugs upon placental amino acid transport . with human placenta cocaine ( or a combination of cocaine and nicotine ) reduced maternal - fetal transport of amino acids mediated by system l , system a , and system y transporters . taurine is regarded as essential for the fetus because the ability to synthesize this amino acid is low or absent during fetal life . the taurine transporter ( system  , taut ; slc6a6 ) mediates cellular taurine uptake against its concentration gradient energized by cotransport with sodium and chloride . activity of the taurine transporter has been reported as reduced in mvm , but not bm , isolated from iugr placentas .   in pregnancies complicated by iugr , it is believed that the placenta is subjected to oxidative stress   and fetal nitric oxide levels ( measured in venous umbilical cord blood ) are elevated . the nitric oxide donor sin-1 has been shown to reduce taurine transport in both isolated mvm vesicles and villous tissue explants [ 65 , 93 ] . uptake of taurine in villous tissue from human placenta is not affected by cytokines or hormones , such as igf - i and ii , il-1 , il-6 , gh , leptin , or tnf- . furthermore , taurine uptake in villous tissue explants was not affected by inhibiting mtor . in contrast , mtor has been shown to be a positive regulator of taurine transport in cultured trophoblast cells ; it also affects mrna expression of this transporter [ 46 , 54 ] . . the effect may be independent of mtor because glucose deprivation stimulates taurine uptake both in the absence and presence of rapamycin . fatty acids are a source of energy , constitute an essential structural element of cellular membranes , and are precursors for important bioactive compounds . for instance , in the third trimester , fat rapidly accumulates in fetal adipose tissue and brain . the long - chained polyunsaturated fatty acids ( lcpufas ) are of particular importance for brain development [ 108 , 109 ] . fatty acids taken up by the placenta and transported to the fetus originate predominantly from two sources in maternal circulation : nonesterified fatty acids ( nefas ) and esterified fatty acids in triglycerides ( tgs ) carried by lipoproteins . maternal tgs have been suggested as a primary source of fatty acids because of their substantial increase in late gestation compared to nefas . fatty acids ( in the form of tgs ) transported in maternal lipoproteins are made available for placental transport by hydrolysis into nefas . the placenta expresses several lipases , two of which function in the extracellular compartment : lipoprotein lipase ( lpl ; lpl ) and endothelial lipase ( el ; lipg ) which is consistent with reports of two different lipase activities identified in isolated mvm vesicles . lpl activity and/or expression in cultured trophoblast cells , mvm vesicles , or placental villous tissue have been reported by several groups [ 66 , 67 , 79 , 81 , 89 , 110112 ] . however , conflicting data on localization of lpl to the syncytiotrophoblast in term placenta exists . lpl activity per gram tissue in villous explants from term placenta is higher compared to first trimester , suggesting placental lpl activity increases with advancing gestation . pregnancy complications also affect placental lpl . the mrna expression of lpl is increased , but measurable placental lpl activity is reduced in iugr babies born preterm . lpl activity is increased in mvm isolated from placenta of pregnancies complicated by maternal insulin - dependent diabetes with fetal overgrowth . placental lpl activity is reduced by chronic exposure to cortisol , estradiol , igf - i , or insulin . shorter exposures to physiological concentrations of estradiol and insulin in combination with hyperglycemia increase lpl activity . in cultured trophoblast cells , the mechanism for the reduced activity is unknown , but it may occur through displacement of the lpl enzyme from its extracellular anchoring site . cytokines have been shown to regulate lpl activity in other tissues ; however , tnf- does not modulate lpl activity in villous explants   or in cultured trophoblast cells . in addition , maternal late pregnancy il-6 levels are inversely correlated with placental lpl activity at term . however , in cultured trophoblast cell experiments , il-6 does not directly regulate activity of this lipase . collectively , these data suggest that placental lpl is not regulated by proinflammatory cytokines . while lpl primarily hydrolyses tgs in chylomicrons and very low - density lipoprotein particles , high - density lipoprotein phospholipids are the preferred substrate of el . in placenta , both endothelial cells and the syncytiotrophoblast have been reported to express el . the el expression changes during pregnancy ; term placenta expresses higher levels of el than first trimester placenta , and pregnancy complications have also been shown to influence placental el expression . maternal obesity combined with gestational diabetes results in higher placental expression of el ; contrastingly , placentas of iugr pregnancies have decreased el expression . transfer of fatty acids from mother to fetus may be driven by the maternal to fetal concentration gradient . nefas may cross lipid bilayers by simple diffusion , but to what degree cells rely on this diffusion for fatty acid uptake is unclear [ 115117 ] . in tissues with high fatty acid demand , uptake of fatty acids by simple to what extent nefas diffuse across the syncytiotrophoblast 's plasma membranes and contribute to fatty acid transfer to the fetus is currently unknown . preferential accumulation ( biomagnification ) of lcpufas in the fetal compartment [ 119 , 120 ] is consistent with a mediated transport of these fatty acids . there is evidence for selective transport of lcpufas in cell culture models [ 121 , 122 ] and perfused placenta , as well as from in vivo studies with docosahexaenoic acid ( dha ) labeled with stable isotopes . fatty acid transport proteins ( fatps ) are integral membrane proteins important for cellular uptake of long - chained fatty acids . the fatp family consists of six related members , of which five are expressed in human placenta ( fatp1 - 4 , and 6 ; slc27a1 - 4 , and 6 ) . at the mrna level , fatp2 , fatp4 , and fatp6 fatp1 protein expression has been demonstrated in both bm and mvm [ 127 , 128 ] , but cellular localization of the other isoforms in placenta is currently unknown . placental fatp1 and fatp4 mrna expression correlates with dha levels in both maternal plasma and placental phospholipids . only fatp4 mrna expression correlated with fetal dha phospholipid levels , suggesting fatp4 is particularly important for placental lcpufa transfer . studies exploring mechanisms regulating placental fatps have been focused primarily on mrna expression levels . in cultured trophoblast cells from term placenta , peroxisome proliferator - activated receptor ( ppar)/retinoid x receptor signaling and hypoxia regulate fatp1 , fatp2 , and fatp4 mrna expression [ 125 , 126 ] . in the same model , fatp4 mrna expression was shown to be downregulated by chronic exposure to il-6 , but without corresponding alteration in protein expression . it has been reported in animal models of maternal obesity that placental mrna expression of fatp1 and fatp4 are increased [ 130 , 131 ] . in addition to fatps , there are two other membrane - associated proteins expressed in placenta with the ability to transport fatty acids : a placenta specific membrane bound fatty acid binding protein ( pfabppm ) and fatty acid translocase ( fat ; cd36 ) . functionally , pfabppm exhibits a high affinity for lcpufas , suggesting this transporter is involved in preferential uptake of these fatty acids for transfer across the placenta . since proportionally less dha and arachidonic acid is transferred to the fetus in iugr pregnancies , but expression of fat is unchanged , a role for fat in selective lcpufa transfer seems unlikely . little is known about regulation of pfabppm and fat in human placenta , but in cultured trophoblast cells , elevated levels of leptin cause an increase in fat expression .   fatty acid binding proteins ( fabps ) within the cytosol of the syncytiotrophoblast traffic fatty acids to sites within the cell for esterification , beta - oxidation , or human placenta expresses four different isoforms of fabps : fabp1 , fabp3 , fabp4 , and fabp5 ( fabp1 , 3 , 4 , and 5 ) . this augmented fabp1 expression together with higher lpl activity has been suggested to contribute to increased fetal fat accumulation in pregnancies complicated by maternal diabetes . in primary human trophoblast cells while fabp3 expression is not altered in pregnancies complicated by iugr or maternal diabetes , fabp4 expression is increased in placenta from obese diabetic women . fetal glucose production is minimal ; therefore , it is entirely dependent upon placental supply of glucose from the maternal circulation . placental transport of glucose is mediated by facilitated carrier - mediated diffusion through specific glucose transporter proteins ( gluts ) . gluts are expressed in both plasma membranes of the syncytiotrophoblast , with glucose transport occurring only down its concentration gradient . a high density of gluts in the mvm , together with the large surface area , allow for rapid glucose uptake into the syncytiotrophoblast . the high capacity of the mvm for glucose transport provides adequate glucose for placental consumption ( corresponding to approximately one - third of total placental glucose uptake ) while maintaining a gradient between the syncytiotrophoblast cell interior and the fetal capillary , which is necessary for net transport to the fetus . the gluts are expressed at a much lower level in the bm than the mvm . the lower bm glut expression , along with the surface area difference , has led to the proposal that bm transport constitutes the rate limiting step in placental glucose transfer . glut1 ( slc2a1 ) is believed to be a primary glucose transporter isoform in the human placenta at term , and its expression increases over gestation . glut1 has been localized to both plasma membranes , but with three - fold higher expression in the mvm . expression of glut1 in bm has been reported to increase in maternal diabetes [ 72 , 138 ] , resulting in increased bm glucose transport activity with this pregnancy complication . glut1 is not the only glucose transporter expressed in human placenta . despite previous reports of little or no glut3 ( slc2a3 ) expression in the syncytiotrophoblast of term placentas [ 136 , 137 , 139 ] , glut3 expression has recently been reported throughout gestation in the syncytiotrophoblast , albeit with the highest expression in early pregnancy . the human placenta also expresses glut8 ( slc2a8 ) , glut9 ( slc2a9 ) , and glut10 ( slc2a10 ) . interestingly , first trimester syncytiotrophoblast also expresses the insulin sensitive glucose transporter isoforms glut4 ( slc2a4 ) and glut12 ( slc2a12 ) [ 136 , 144 ] . placental glucose uptake increases with advancing gestation , and regulation of glucose transport differs between trimesters . however , gh has no effect on glucose uptake in first trimester villous fragments . in cultured trophoblast cells from term placenta , crh has opposing effects on glut1 and glut3 expression ( increased glut1 and decreased glut3 ) . crh can act through two different receptors : crh - r1 and crh - r2 . crh - r1 expression decreases in iugr placenta , and in cultured trophoblast cells , crh - r1 positively regulates glut1 expression . because crh is produced locally in the placenta , such data is consistent with autocrine / paracrine regulation of placental glucose transport mediated by crh . steroid hormones can also affect activity / expression of placental glucose transporters in term placenta . in studies measuring glucose uptake in isolated mvm vesicles , estrogens and progesterone were found to have a negative impact on glucose uptake rates . in cultured trophoblast cells the effect of insulin on regulating placental glucose transport is gestational age dependent , and there are conflicting reports on its effects at term . insulin does not affect glucose uptake in perfused term placenta   or in term villous fragments [ 39 , 136 ] . however , other investigators have reported stimulation of placental glucose uptake by insulin at term [ 83 , 84 ] . ericsson and coworkers found that insulin stimulates glucose uptake in villous fragments from first trimester placenta but not from term placenta . this observation could be due to the finding that glut4 and 12 , two insulin - sensitive isoforms , are expressed in first trimester [ 136 , 144 ] but not term placenta . exposing cultured trophoblast cells to hyperglycemia reduced uptake rates and glut1 expression . depriving the cells of glucose has the opposite effect , causing increased uptake and expression of glut1 . oxidative stress not only affects placental transport of amino acids [ 65 , 93 ] , but can also influence transport of glucose . in placental explants , increased oxidative stress resulted in reduced glucose uptake and lowered glut1 expression . in bewo cells , chronic hypoxia in vivo with high altitude pregnancies reduces expression of glut1 in bm but not in mvm . they are also intimately linked with increased risk for development of metabolic disease later in life . changes in placental nutrient transport capacity with altered fetal growth , and regulation of placental transport functions by maternal and fetal signaling molecules , have been extensively studied ( in villous explants , cultured trophoblast cells , and animal models ) . measurements of circulating factors in human pregnancies complicated by abnormal fetal growth are of particular interest because , together with the information on factors regulating placental nutrient transport reviewed here , such data allows identification of key factors regulating placental function in vivo . it is important to note that because the placenta produces many cytokines and hormones that could act in paracrine or autocrine fashion , the circulating levels may not be representative of concentrations in the intervillous space . we have proposed that alterations in maternal nutrient supply , adipokine , cytokine , and hormone levels such as those found in common pregnancy complications can lead to modification in placental transport function and subsequently have effects on fetal growth . signals of reduced maternal nutrient availability ( e.g. , low insulin and leptin , high adiponectin ) lead to an overall reduction in nutrient delivery to the fetus and slow fetal growth , while maternal signals of good nutritional status ( such as high insulin and leptin , low adiponectin ) stimulate nutrient delivery and accelerate fetal growth . candidate regulatory factors and their effects on placental macronutrient transport functions are summarized in table 2 . however , nutrient transporters are specifically regulated and regulatory factors may have opposing effects on different transport systems , while rendering other transporters unaffected . integration of multiple stimuli is critical for adjusting placental function to accommodate maternal supply and fetal demand . trophoblast cells must integrate numerous , possibly divergent , maternal and fetal stimuli and modify cellular function accordingly . three examples of key placental signaling pathways involved with integrating multiple signals and regulating nutrient transport are ( 1 ) stat3 , involved in modulation of amino acid transport by cytokines , ( 2 ) ppar affecting expression of fabps and fatps , and ( 3 )  mtor signaling pathway regulating placental amino acid transport ( figure 2 ) . additionally , altered activity and/or expression of placental mtor and ppar have been demonstrated in human pregnancies complicated by altered fetal growth [ 50 , 51 , 53 , 151 ] . the origins of altered fetal growth are likely multifactorial , investigating single component effects will shed light on individual components as potential contributing factors . yet , how such components orchestrate a unified response , modify placental nutrient transport , and regulate fetal growth remains to be established . alterations in fetal development and growth have been associated with lifelong adverse health consequences . since fetal growth and placental nutrient transport are closely linked , a cohesive knowledge of placental nutrient transport regulation will most certainly bring us closer to understanding those mechanisms underlying altered fetal growth . as reviewed in this paper , research has predominantly focused upon how individual factors , known to change in pregnancies complicated by pathological fetal growth , affect nutrient transport across the syncytiotrophoblast . this research resulted in the discovery of novel mechanisms involved in the regulation of placental nutrient transport . however , further work is needed which elucidates how multiple fetal , maternal , and placental signals are integrated and together regulate nutrient transport from mother to fetus .
abnormal fetal growth , both growth restriction and overgrowth , is associated with perinatal complications and an increased risk of metabolic and cardiovascular disease later in life . 
 fetal growth is dependent on nutrient availability , which in turn is related to the capacity of the placenta to transport these nutrients . 
 the activity of a range of nutrient transporters has been reported to be decreased in placentas of growth restricted fetuses , whereas at least some studies indicate that placental nutrient transport is upregulated in fetal overgrowth . 
 these findings suggest that changes in placental nutrient transport may directly contribute to the development of abnormal fetal growth . 
 detailed information on the mechanisms by which placental nutrient transporters are regulated will therefore help us to better understand how important pregnancy complications develop and may provide a foundation for designing novel intervention strategies . in this paper we will focus on recent studies of regulatory mechanisms that modulate placental transport of amino acids , fatty acids , and glucose .