Placental Fatty Acid Transport Research Articles

High-fat diet during pregnancy promotes fetal skeletal muscle fatty acid oxidation and insulin resistance in an ovine model.

Maternal diet during pregnancy is associated with offspring metabolic risk trajectory in humans and animal models, but the prenatal origins of these effects are less clear. We examined the effects of a high-fat diet (HFD) during pregnancy on fetal skeletal muscle metabolism and metabolic risk parameters using an ovine model. White-faced ewes were fed a standardized diet containing 5% fat wt/wt (CON), or the same diet supplemented with 6% rumen-protected fats (11% total fat wt/wt; HFD) beginning 2 wk before mating until midgestation (GD75). Maternal HFD increased maternal weight gain, fetal body weight, and low-density lipoprotein levels in the uterine and umbilical circulation but had no significant effects on circulating glucose, triglycerides, or placental fatty acid transporters. Fatty acid (palmitoylcarnitine) oxidation capacity of permeabilized hindlimb muscle fibers was >50% higher in fetuses from HFD pregnancies, whereas pyruvate and maximal (mixed substrate) oxidation capacities were similar to CON. This corresponded to greater triacylglycerol content and protein expression of fatty acid transport and oxidation enzymes in fetal muscle but no significant effect on respiratory chain complexes or pyruvate dehydrogenase expression. However, serine-308 phosphorylation of insulin receptor substrate-1 was greater in fetal muscle from HFD pregnancies along with c-jun-NH2 terminal kinase activation, consistent with prenatal inhibition of skeletal muscle insulin signaling. These results indicate that maternal high-fat feeding shifts fetal skeletal muscle metabolism toward a greater capacity for fatty acid over glucose utilization and favors prenatal development of insulin resistance, which may predispose offspring to metabolic syndrome later in life.NEW & NOTEWORTHY Maternal diet during pregnancy is associated with offspring metabolic risk trajectory in humans and animal models, but the prenatal origins of these effects are less clear. This study examined the effects of a high-fat diet during pregnancy on metabolic risk parameters using a new sheep model. Results align with findings previously reported in nonhuman primates, demonstrating changes in fetal skeletal muscle metabolism that may predispose offspring to metabolic syndrome later in life.

Developmental toxicity of perfluorohexane sulfonate at human relevant dose during pregnancy via disruption in placental lipid homeostasis

Perfluorohexyl sulfonate (PFHxS) is the third most abundant per- and polyfluoroalkyl substances and its developmental toxicity remains very poorly understood. Here, pregnant mice exposed to PFHxS at human relevant dose showed increased fetal death incidence in the high-dose PFHxS-H group (P < 0.01). Body distribution analyses suggested that PFHxS crossed the placental barrier reaching the fetus in a dose-dependent manner. Histopathological data demonstrated impairment in the placenta with reduced blood sinus volume, placental labyrinth area as well as thickness of labyrinthine layer. Further lipidomic and transcriptomic data together showed that PFHxS exposure caused significant disruption in placental lipid homeostasis, including total lipid accumulation in the placenta, and dysregulation in phospholipid and glycerol lipid metabolism. Gene expression analyses uncovered elevation in key placental fatty acid transporters including fabp2, whereas protein expression showed transporter specific disruptions following exposure. Together, gestational exposure to human relevant level of PFHxS may increase the incidence of fetal deaths and caused placental dysplasia via disruption in lipid metabolism homeostasis. These findings raise the concern regarding the highly prevalent and persistent chemical towards early sensitive developing stages and provide basis for further understanding of its effects on lipid metabolism and underlying mechanisms.

Placental Fatty Acid Metabolism and Transport in a Rat Model of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a form of heightened insulin resistance triggered during gestation. This study examines how insulin resistance alters placental long-chain polyunsaturated fatty acid (LCPUFA) transport and metabolism in a rat model of lean GDM. Pregnant Sprague Dawley rats were administered with S961, an insulin receptor antagonist (30 nmol/kg s.c. daily), or vehicle from gestational day (GD) 7 to 20. Daily maternal body weight, food, and water intake were measured. Blood pressure assessment and glucose tolerance test were done on GD20. Fetal plasma and placenta were collected on GD20 and processed for fatty acid measurement using LC-mass spectrometry. The expression of fatty acid metabolism-related genes in the placenta was assessed using RT2 Profiler PCR arrays. The results were validated by qRT-PCR. Blockade of insulin receptors with S961 in pregnant rats resulted in glucose intolerance with increased fasting glucose and insulin levels. Maternal body weight gain and food and water intake were not affected; however, S961 significantly increased maternal blood pressure and heart rate. The placenta n3 and n6 LCPUFA concentrations were significantly decreased by 8% and 11%, respectively, but their levels in the fetal plasma were increased by 15% and 4%. RT2 profiler arrays revealed that placental expressions of 10 genes related to fatty acid β-oxidation (Acaa1a, Acadm, Acot2, Acox2, Acsbg1, Acsl4, Acsm5, Cpt1b, Eci2, Ehhadh) and 3 genes related to fatty acid transport pathway (Fabp2, Fabp3, Slc27a3) were significantly upregulated. In summary, lack of insulin action increased the expression of genes related to placental fatty acid β-oxidation and transport with an increased transfer of LCPUFA to the fetus. The increased lipid levels routed toward the fetus may lead to fat adiposity and later-life metabolic dysfunction.

Maternal Fatty Acid Metabolism in Pregnancy and Its Consequences in the Feto-Placental Development.

During pregnancy, maternal plasma fatty acids are critically required for cell growth and development, cell signaling, and the development of critical structural and functional aspects of the feto-placental unit. In addition, the fatty acids modulate the early stages of placental development by regulating angiogenesis in the first-trimester human placenta. Preferential transport of maternal plasma long-chain polyunsaturated fatty acids during the third trimester is critical for optimal fetal brain development. Maternal status such as obesity, diabetes, and dietary intakes may affect the functional changes in lipid metabolic processes in maternal-fetal lipid transport and metabolism. Fatty acids traverse the placental membranes via several plasma membrane fatty acid transport/binding proteins (FAT, FATP, p-FABPpm, and FFARs) and cytoplasmic fatty acid-binding proteins (FABPs). This review discusses the maternal metabolism of fatty acids and their effects on early placentation, placental fatty acid transport and metabolism, and their roles in feto-placental growth and development. The review also highlights how maternal fat metabolism modulates lipid processing, including transportation, esterification, and oxidation of fatty acids.

Maternal High-Fat Diet Increases Fetal Muscle Fat Metabolism and Fatty Acid Transporter Expression in an Ovine Model

ObjectivesExcessive maternal dietary fat consumption during pregnancy may be linked to adverse effects on offspring health, including greater risk of developing metabolic syndrome later in life. Metabolic syndrome is generally considered to be a preventable condition, but the extent to which it is “programmed” during fetal development remains unclear. The aim of this study was to determine the effect of a maternal high-fat diet (MHFD) during pregnancy on fetal muscle oxidative metabolism and related protein and mRNA expressions in an ovine model. MethodsWhite-faced ewes were fed either a control diet (Show-rite NewCo Lamb Feed-17% protein, 5% Fat) or a high-fat diet (Show-rite NewCo Lamb Feed + 6% Rumen-protected Fat) from 2–3 weeks before pregnancy until mid-gestation (75 days), when a C-section was performed to collect the placenta and fetal tissues for analysis. ResultsMHFD tended to increase fetal body and organ weights, but only significantly increased fetal body length and liver mass (P < 0.05). MHFD increased mRNA expression of placental (cotyledon) fatty acid transport protein-1 (FATP-1) and peroxisome proliferator activated receptor gamma, suggesting an upregulation of placental fatty acid metabolism and transport. Fetal muscle fatty acid oxidation capacity was greater in animals from MHFD pregnancies, with no effect on pyruvate oxidation. This was associated with greater fetal muscle mRNA and protein expression of FATP4, while mRNA expression glucose transporters (GLUT1 and GLUT3) decreased. Muscle expression of insulin signaling enzymes reflected a mild decreases in insulin sensitivity, but these did not reach statistical significance. ConclusionsThese studies indicate that MHFD induces an increase in placental and fetal muscle fatty acid transport and oxidation capacity, and favors lower blood glucose uptake compared to controls. Whether these shifts in fetal metabolism predispose offspring from MHFD pregnancies to elevated blood sugar and Type 2 diabetes later in life merits further investigation. Funding SourcesColorado Agricultural Experiment Station.

Sex-specific responses in placental fatty acid oxidation, esterification and transfer capacity to maternal obesity

Fatty acid metabolism and oxidation capacity in the placenta, which likely affects the rate and composition of lipid delivered to the fetus remains poorly understood. Long chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), are critical for fetal growth and brain development. We determined the impact of maternal obesity on placental fatty acid oxidation, esterification and transport capacity by measuring PhosphatidylCholine (PC) and LysoPhosphatidylCholine (LPC) containing DHA by mass spectrometry in mother-placenta-baby triads as well as placental free carnitine and acylcarnitine metabolites in women with normal and obese pre-pregnancy BMI. Placental protein expression of enzymes involved in beta-oxidation and esterification pathways, MFSD2a (lysophosphatidylcholine transporter) and OCTN2 (carnitine transporter) expression in syncytiotrophoblast microvillous (MVM) and basal (BM) membranes were determined by Western Blot. Maternal obesity was associated with decreased umbilical cord plasma DHA in LPC and PC fractions in male, but not female, fetuses. Basal membrane MFSD2a protein expression was increased in placenta of males of obese mothers. In female placentas, despite an increased MVM OCTN2 expression, maternal obesity was associated with a reduced MUFA-carnitine levels and increased esterification enzymes. We speculate that lower DHA-PL in fetal circulation of male offspring of obese mothers, despite a significant increase in transporter expression for LPC-DHA, may lead to low DHA needed for brain development contributing to neurological consequences that are more prevalent in male children. Female placentas likely have reduced beta-oxidation capacity and appear to store FA through greater placental esterification, suggesting impaired placenta function and lipid transfer in female placentas of obese mothers.

Placental lipid metabolism in preeclampsia.

The current study examines the placental and maternal lipid profile and expression of genes involved in placental lipid metabolism in women with preeclampsia. The current study includes normotensive control women (n = 40) and women with preeclampsia (n = 39). Preeclampsia women were further classified into women delivering at term preeclampsia (T-PE; n = 15) and preterm preeclampsia (PT-PE; n = 24). There were no significant differences in maternal lipid profile between the T-PE and normotensive control groups. Maternal plasma VLDL (P < 0.05) and ratios of total cholesterol : HDL (P < 0.05), atherogenic index [log (triglycerides/HDL)] (P < 0.01) and apolipoprotein B : apolipoprotein A (P < 0.05) were higher in the PT-PE group as compared with the normotensive control group. Placental total cholesterol and HDL levels were higher (P < 0.05) in the T-PE as compared with the normotensive control group. Higher placental triglycerides (P < 0.05) were observed in PT-PE group compared with T-PE group. Placental mRNA levels of peroxisome proliferator activated receptor α, carnitine palmitoyl transferase-1, cluster of differentiation 36 and lipoprotein lipases were lower (P < 0.05) in the PT-PE than normotensive control group. A negative association of mRNA levels of peroxisome proliferator activated receptor α (r = -0.246, P = 0.032; r = -0.308, P = 0.007, respectively), carnitine palmitoyl transferase-1 (r = -0.292, P = 0.011; r = -0.366, P = 0.001), lipoprotein lipases (r = -0.296, P = 0.010; r = -0.254, P = 0.028) with SBP and DBP was observed. There was a positive association of placental triglycerides (r = 0.244, P = 0.031) with DBP. Women with preeclampsia exhibit higher lipid : lipoprotein ratios suggesting an atherogenic state particularly in women delivering preterm. Lower expression of genes involved in placental fatty acid oxidation and transport was also observed in preeclampsia.

Maternal High Linoleic Acid Alters Placental Fatty Acid Composition.

Fetal development is modulated by maternal nutrition during pregnancy. The dietary intake of linoleic acid (LA), an essential dietary n-6 polyunsaturated fatty acid (PUFA), has increased. We previously published that increased LA consumption during pregnancy does not alter offspring or placental weight but fetal plasma fatty acid composition; the developing fetus obtains their required PUFA from the maternal circulation. However, it is unknown if increased maternal linoleic acid alters placental fatty acid storage, metabolism, transport, and general placental function. Female Wistar-Kyoto rats were fed either a low LA diet (LLA; 1.44% of energy from LA) or high LA diet (HLA; 6.21% of energy from LA) for 10 weeks before pregnancy and during gestation. Rats were sacrificed at embryonic day 20 (E20, term = 22 days) and placentae collected. The labyrinth of placentae from one male and one female fetus from each litter were analyzed. High maternal LA consumption increased placental total n-6 and LA concentrations, and decreased total n-3 PUFA, alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA). Fatty acid desaturase 1 (Fads1), angiopoietin-like 4 (Angptl4), and diacylglycerol lipase beta (Daglb) mRNA were downregulated in placentae from offspring from HLA dams. Maternal high LA downregulated the fatty acid transport protein 4 (Fatp4) and glucose transporter 1 (Slc2a1) mRNA in placentae. IL-7 and IL-10 protein were decreased in placentae from offspring from HLA dams. In conclusion, a high maternal LA diet alters the placental fatty acid composition, inflammatory proteins, and expressions of nutrient transporters, which may program deleterious outcomes in offspring.

Placental fatty acid transport across late gestation in a baboon model of intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and increased risk of lifelong disease, including neurodevelopmental impairment. Fatty acids (FA) are critical for normal brain development, although their transport across the placenta in IUGR pregnancies is poorly understood. The present study used a baboon model of IUGR (maternal nutrient restriction, MNR) to investigate placental expression of FA transport and binding proteins, and to determine gestational age-related changes in maternal and fetal plasma FA concentrations. We found MNR to be associated with increased placental expression of FA binding and transport proteins in late gestation, with fetal plasma FA concentrations that were similar to those of control animals. The present study is the first to report a profile of fetal and maternal plasma FA concentrations in a baboon model of growth restriction with data that suggest adaptation of placental transport to maintain delivery of critically needed FA. Intrauterine growth restriction (IUGR) is associated with specific changes in placental transport of amino acids, folate and ions. However, little is known about placental fatty acid (FA) transport in IUGR. We hypothesized that placental FA transport proteins (FATP) and FA binding proteins (FABP) are up-regulated and fetal plasma FA concentrations are decreased at term in a baboon model of IUGR. Pregnant baboons were fed control or maternal nutrient restricted (MNR) diet (70% of control calories) from gestation day (GD) 30 (term 184days). Plasma and placental samples were collected at GD120 (control n=8, MNR n=9), GD140 (control n=6, MNR n=7) and GD170 (control n=6, MNR n=6). Placentas were homogenized, and syncytiotrophoblast microvillous plasma membrane (MVM) and basal plasma membranes (BM) were isolated. Protein expression of FABP1, 3, 4 and 5 (homogenate) and FATP2, 4, and 6 (MVM, BM) was determined by Western blotting. FA content in maternal and umbilical vein plasma was measured by gas chromatography-mass spectrometry. Placental FABP1 and FABP5 expression was increased in MNR compared to controls at GD170, as was MVM FATP2 and FATP6 expression at GD140 and FATP2 expression at GD170. BM FATP4 and FATP6 expression was increased in MNR at GD140. Fetal plasma FA concentrations were similar in controls and MNR. These data suggest the adaptation of placental transport when aiming to maintain delivery of critically needed FAs for fetal growth and brain development.

The effect of high glucose on lipid metabolism in the human placenta

Diabetes mellitus (DM) during pregnancy can result in fetal overgrowth, likely due to placental dysfunction, which has health consequences for the infant. Here we test our prediction from previous work using a placental cell line that high glucose concentrations affect placental lipid metabolism. Placentas from women with type 1 (n = 13), type 2 (n = 6) or gestational (n = 12) DM, BMI-matched to mothers without DM (n = 18), were analysed for lipase and fatty acid transport proteins and fatty acid and triglyceride content. Explants from uncomplicated pregnancies (n = 6) cultured in physiological or high glucose were similarly analysed. High glucose levels did not alter placental lipase or transporter expression or the profile and abundance of fatty acids, but triglyceride levels were higher (p < 0.05), suggesting reduced β- oxidation. DM did not affect placental protein expression or fatty acid profile. Triglyceride levels of placentas from mothers with pre-existing DM were similar to controls, but higher in obese women with gestational DM. Maternal hyperglycemia may not affect placental fatty acid uptake and transport. However, placental β-oxidation is affected by high glucose and reduced in a subset of women with DM. Abnormal placental lipid metabolism could contribute to increased maternal-fetal lipid transfer and excess fetal growth in some DM pregnancies.

Cloned pig fetuses exhibit fatty acid deficiency from impaired placental transport.

Cloned pig fetuses produced by somatic cell nuclear transfer show a high incidence of erroneous development in the uteri of surrogate mothers. The mechanisms underlying the abnormal intrauterine development of cloned pig fetuses are poorly understood. This study aimed to explore the potential causes of the aberrant development of cloned pig fetuses. The levels of numerous fatty acids in allantoic fluid and muscle tissue were lower in cloned pig fetuses than in artificial insemination-generated pig fetuses, thereby suggesting that cloned pig fetuses underwent fatty acid deficiency. Cloned pig fetuses also displayed trophoblast hypoplasia and a reduced expression of placental fatty acid transport protein 4 (FATP4), which is the predominant FATP family member expressed in porcine placentas. This result suggested that the placental fatty acid transport functions were impaired in cloned pig fetuses, possibly causing fatty acid deficiency in cloned pig fetuses. The present study provides useful information in elucidating the mechanisms underlying the abnormal development of cloned pig fetuses.

Downregulations of placental fatty acid transporters during cadmium-induced fetal growth restriction

Cadmium (Cd) is one of the environmental pollutants, which has multiple toxic effects on fetuses and placentas. Placental fatty acid (FA) uptake and transport are critical for the fetal and placental development. We aimed to analyze the triglyceride (TG) level, the expression patterns of several key genes involved in FA uptake and transport, and the molecular mechanisms for the altered gene expressions in placentas in response to Cd treatment. Our results showed that the placental TG level was significantly decreased in the Cd-exposed placentas. Fatty acid transporting protein 1 (FATP1), FATP6 and fatty acid binding protein 3 (FABP3) were significantly down-regulated in the placentas from Cd-exposed mice. The expression level of phospho-p38 MAPK was increased by Cd treatment, while the protein level of total p38 MAPK remained unchanged. The expression levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) and the hypoxia-inducible factor-1α (HIF-1α) were significantly decreased in the Cd-exposed placentas. The methylation levels of the promoter regions of FATP1, FATP6 and FABP3 showed no significant differences between the treatment and control groups. In addition, the circulating non-esterified fatty acid (NEFA), total cholesterol (TC), and TG levels were not decreased in the maternal serum from the Cd-exposed mice. Therefore, our results suggest Cd exposure dose not reduce the maternal FA supply, but reduces the placental TG level. Cd treatment also downregulates the placental expressions of FATP1, FATP6 and FABP3, respectively associated with p38-MAPK, p38 MAPK/PPAR-γ and HIF-1α pathways.

Linoleic Acid Increases Prostaglandin E2 Release and Reduces Mitochondrial Respiration and Cell Viability in Human Trophoblast-Like Cells.

The omega 6 fatty acid (FA) linoleic acid (LA) is required for embryonic development; however, omega 6 FAs can alter cellular metabolism via inflammation or modulation of mitochondrial function. Fetal LA is obtained from the maternal diet, and FAs are transported to the fetus via placental FA transporters (FATPs) and binding proteins (FABPs), but specific proteins responsible for LA transport in placental trophoblasts are unknown. Dietary LA consumption is increasing, but the effect of elevated LA on trophoblast function is not clear. Swan71 trophoblasts were exposed to physiological and supraphysiological concentrations of LA for 24 hours. Quantification of mRNA was determined using real time PCR, and protein concentration was determined by Western blot analysis. Cell viability, citrate synthase activity and mitochondrial respiration were determined. Exposure to 300 and 500 μM LA increased FATP1 and FATP4 mRNA expression. 500 μM LA increased FATP1 and FATP4 protein expression. Exposure to 500 μM increased FABP5 mRNA expression, while exposure to 100 to 500 μM LA decreased FABP3 mRNA expression. 300 and 500 μM LA decreased FABP3 protein expression. Cell viability was decreased by exposure to LA (100 to 1000 μM). Citrate synthase activity and routine mitochondrial respiration were significantly decreased by exposure to 300 and 500 μM LA, and maximal respiration and spare respiratory capacity were decreased by exposure to 100 to 500 μM LA. 300 and 500 μM LA increased reactive oxygen species generation in human trophoblasts. Moreover, exposure to 300 and 500 μM LA decreased IL-6 secretion. Exposure to 500 μM LA increased IL-8, NF-κB and PPAR-γ mRNA expression, but decreased NF-κB protein expression. 300 μM LA decreased IL-8 protein expression. Further, exposure to 100 to 500 μM LA increased prostaglandin E2 and leukotriene B₄ release. Exposure to LA decreases cell viability, alters mRNA expression of FA transport related proteins, mitochondrial respiration and function, and inflammatory responses in trophoblasts. These findings may have implications on placental function when women consume high levels of LA.

Downregulation of peroxisome proliferator-activated receptor gamma in the placenta correlates to hyperglycemia in offspring at young adulthood after exposure to gestational diabetes mellitus.

Aims/IntroductionChildren who are exposed to gestational diabetes mellitus (GDM) in utero are at high risk of developing related illnesses, such as type 2 diabetes mellitus in young adulthood, but the underlying mechanism and related predictive biomarkers are not known.Materials and MethodsThe present study identified the related biomarkers of hyperglycemia in young adults from the relationship between fetal blood glucose and placental lipid transporters at messenger ribonucleic acid (mRNA) and protein expression levels. We recruited patients from a prospective cohort, and determined the mRNA and protein levels of placental fatty acid transporters. Diet‐induced mouse models of GDM were established, and the mRNA and protein levels of the same transporters in placentas were validated.ResultsOnly the mRNA levels of peroxisome proliferator‐activated receptor gamma correlated with the levels of neonatal blood glucose in GDM patients using linear regression and Spearman's correlation analyses (r = 0.774, P = 0.001). The mRNA levels of peroxisome proliferator‐activated receptor gamma, matrix metalloproteinase‐2 and fatty acid transport protein‐6 correlated with blood glucose levels in mouse offspring (r = 0.82, P = 0.001, r = 0.737, P = 0.006 and r = −0.891, P = 0.001, respectively) at young adulthood using the same analyses. Notably, we observed significantly higher blood glucose levels in GDM offspring at 12 weeks‐of‐age compared with the control and rosiglitazone‐supplemented groups (P < 0.05).ConclusionsThe downregulation of peroxisome proliferator‐activated receptor gamma in the placenta might predict hyperglycemia in offspring at young adulthood.

Real-time microscopic assessment of fatty acid uptake kinetics in the human term placenta

IntroductionThe placenta employs an efficient and selective fatty acid transport system to supply lipids for fetal development. Disruptions in placental fatty acid transport lead to restricted fetal growth along with cardiovascular and neurologic deficits. Nevertheless, little is known about the molecular mechanisms involved in human placental fatty acid trafficking during the initial steps of uptake, or the importance of fatty acid chain length in determining uptake rates. MethodsWe employed BODIPY fluorophore conjugated fatty acid analogues of three chain lengths, medium (BODIPY-C5), long (BODIPY-C12), and very-long (BODIPY-C16), to study fatty acid uptake in isolated human trophoblast and explants using confocal microscopy. The three BODIPY-labeled fatty acids were added to freshly isolated explants and tracked for up to 30 min. Fatty acid uptake kinetics were quantified in trophoblast (cytotrophoblast and syncytiotrophoblast together) and the fetal capillary lumen. ResultsLong- (BODIPY-C12) and Very long-chain (BODIPY-C16) fatty acids accumulated more rapidly in the trophoblast layer than did medium-chain (BODIPY-C5) whereas BODIPY-C5 accumulated more rapidly in the fetal capillary than did the longer chain length fatty acids. The long-chain fatty acids, BODIPY-C12 and BODIPY-C16, are esterified and stored in lipid droplets in the cytotrophoblast layer, but medium-chain fatty acid, BODIPY-C5, is not. DiscussionFatty acids accumulate in trophoblast and fetal capillaries inversely according to their chain length. BODIPY-C5 accumulates in the fetal capillary in concentrations far greater than in the trophoblast, suggesting that medium-chain length BODIPY-labeled fatty acids are capable of being transported against a concentration gradient.

Effect of Maternal Obesity on Fetal Growth and Expression of Placental Fatty Acid Transporters.

Objective:To explore the effects of maternal high-fat (HF) diet-induced obesity on fetal growth and the expression of placental nutrient transporters.Methods:Maternal obesity was established in rats by 8 weeks of pre-pregnancy fed HF diet, while rats in the control group were fed normal (CON) diet. Diet-induced obesity (DIO) rats and diet-induced obesity-resistant (DIR) rats were selected according to body weight gain over this period. After copulation, the CON rats were divided into two groups: switched to HF diet (CON-HF group) or maintained on the CON diet (CON-CON group). The DIO rats and DIR rats were maintained on the HF diet throughout pregnancy. Pregnant rats were euthanized at day 21 gestation, fetal and placental weights were recorded, and placental tissue was collected. Reverse transcription-polymerase chain reaction was used to determine mRNA expression of placental nutrient transporters. Protein expression was determined by Western blot.Results:Average fetal weight of DIO dams was reduced by 6.9%, and the placentas of CON-HF and DIO dams were significantly heavier than the placentas of CON-CON and DIR dams at day 21 of gestation (p<0.05). The fetal/placental weight ratio of DIO dams was significantly reduced compared with the fetal/placental weight ratio of CON-CON dams (p<0.05). The mRNA expression of GLUT-1 and SNAT-2 were not significantly different between groups. The mRNA and protein expression levels of CD36, FATP-1, and FATP-4 in DIO dams were decreased significantly (p<0.05).Conclusion:Maternal obesity induced by a HF diet led to intrauterine growth retardation and down-regulated the expression of placental fatty acid transporters.

Effect of Kampo Extract Formulation (Japanese Traditional Medicine) on Pro- and Anti-angiogenic Factors Secreted from Primary Endothelial Cells and Placental Cells

The placenta employs an efficient and selective fatty acid transport system to supply lipids for fetal development. Disruptions in placental fatty acid transport lead to restricted fetal growth along with cardiovascular and neurologic deficits. Nevertheless, little is known about the molecular mechanisms involved in human placental fatty acid trafficking during the initial steps of uptake, or the importance of fatty acid chain length in determining uptake rates.We employed BODIPY fluorophore conjugated fatty acid analogues of three chain lengths, medium (BODIPY-C5), long (BODIPY-C12), and very-long (BODIPY-C16), to study fatty acid uptake in isolated human trophoblast and explants using confocal microscopy. The three BODIPY-labeled fatty acids were added to freshly isolated explants and tracked for up to 30 min. Fatty acid uptake kinetics were quantified in trophoblast (cytotrophoblast and syncytiotrophoblast together) and the fetal capillary lumen.Long- (BODIPY-C12) and Very long-chain (BODIPY-C16) fatty acids accumulated more rapidly in the trophoblast layer than did medium-chain (BODIPY-C5) whereas BODIPY-C5 accumulated more rapidly in the fetal capillary than did the longer chain length fatty acids. The long-chain fatty acids, BODIPY-C12 and BODIPY-C16, are esterified and stored in lipid droplets in the cytotrophoblast layer, but medium-chain fatty acid, BODIPY-C5, is not.Fatty acids accumulate in trophoblast and fetal capillaries inversely according to their chain length. BODIPY-C5 accumulates in the fetal capillary in concentrations far greater than in the trophoblast, suggesting that medium-chain length BODIPY-labeled fatty acids are capable of being transported against a concentration gradient.

Increased placental fatty acid transporter 6 and binding protein 3 expression and fetal liver lipid accumulation in a mouse model of obesity in pregnancy.

Obesity in pregnancy is associated with increased fetal growth and adiposity, which, in part, is determined by transplacental nutrient supply. Trophoblast uptake and intracellular trafficking of lipids are dependent on placental fatty acid transport proteins (FATP), translocase (FAT/CD36), and fatty acid binding proteins (FABP). We hypothesized that maternal obesity in mice leads to increased placental expression of FAT/CD36, FATPs, and FABPs, and lipid accumulation in the fetal liver. C57/BL6J female mice were fed either a control (C; n = 10) or an obesogenic (OB; n = 10) high-fat, high-sugar diet before mating and throughout pregnancy. At E18.5, placentas and fetal livers were collected. Trophoblast plasma membranes (TPM) were isolated from placental homogenates. Expression of FAT/CD36 and FATP (TPM) and FABP (homogenates) was determined by immunoblotting. Gene expression was assessed by RT-quantitative PCR. Sections of fetal livers were stained for Oil Red O, and lipid droplets were quantified. TPM protein expression of FAT/CD36, FATP 2, and FATP 4 was comparable between C and OB groups. Conversely, TPM FATP 6 expression was increased by 35% in OB compared with C placentas without changes in mRNA expression. FABPs 1, 3-5 and PPARγ were expressed in homogenates, and FABP 3 expression increased 27% in OB compared with C placentas; however, no changes were observed in mRNA expression. Lipid droplet accumulation was 10-fold higher in the livers of fetuses from OB compared with C group. We propose that increased lipid transport capacity in obese mice promotes transplacental fatty acid transport and contributes to excess lipid accumulation in the fetal liver.

191: Modulation of fatty acid metabolism by maternal obesity in the human full-term placenta

The fetus is largely dependent on the placenta for its lipid supply. The mechanism that regulates placental fatty acid (FA) transport and metabolism is partially understood. Because placentas of obese mothers accumulate lipids, we hypothesize that FA esterification is higher and FA oxidation is lower in placentas from obese compared with lean women. Therefore, this study investigated markers of placental lipid metabolism in neonates born to obese and lean women.

Fatty Acid Binding Protein 3 Is Involved in n–3 and n–6 PUFA Transport in Mouse Trophoblasts

Background:Low placental fatty acid (FA) transport during the embryonic period has been suggested to result in fetal developmental disorders and various adult metabolic diseases, but the molecular mechanism by which FAs are transported through the placental unit remains largely unknown. Objective:The aim of this study was to examine the distribution and functional relevance of FA binding protein (FABP), a cellular chaperone of FAs, in the mouse placenta. Methods:We clarified the localization of FABPs and sought to examine their function in placental FA transport through the phenotypic analysis of Fabp3-knockout mice. Results:Four FABPs (FABP3, FABP4, FABP5, and FABP7) were expressed with spatial heterogeneity in the placenta, and FABP3 was dominantly localized to the trophoblast cells. In placentas from the Fabp3-knockout mice (both sexes), the transport coefficients for linoleic acid (LA) were significantly reduced compared with those from wild-type mice by 25% and 44% at embryonic day (E) 15.5 and E18.5, respectively, whereas those for α-linolenic acid (ALA) were reduced by 19% and 17%, respectively. The accumulation of LA (18% and 27% at E15.5 and E18.5) and ALA (16% at E15.5) was also significantly less in the Fabp3-knockout fetuses than in wild-type fetuses. In contrast, transport and accumulation of palmitic acid (PA) were unaffected and glucose uptake significantly increased by 23% in the gene-ablated mice compared with wild-type mice at E18.5. Incorporation of LA (51% and 52% at 1 and 60 min, respectively) and ALA (23% at 60 min), but not PA, was significantly less in FABP3-knockdown BeWo cells than in controls, whereas glucose uptake was significantly upregulated by 51%, 50%, 31%, and 33% at 1, 20, 40, and 60 min, respectively. Conclusions:Collectively FABP3 regulates n–3 (ω-3) and n–6 (ω-6) polyunsaturated FA transport in trophoblasts and plays a pivotal role in fetal development.