The fetus requires amino acids for the processes of protein synthesis, carbon accretion, oxidative metabolism, and biosynthesis, which ultimately determine growth rate in utero. The fetal supply of ...amino acids is critically dependent on the transport capacity of the placenta. System A amino acid transporters in the syncytiotrophoblast microvillous plasma membrane, directed toward maternal blood, actively accumulate amino acids, while system L exchangers mediate uptake of essential amino acids from the maternal circulation. The functional capacity and protein abundance of these transporters in the placenta are related to fetal growth in both humans and experimental animals. Maternal nutritional and endocrine signals including insulin, insulin-like growth factors, adipokines, and steroid hormones regulate placental amino acid transport, against the background of growth signals originating from the fetus. Anabolic signals of abundant maternal resource availability stimulate placental amino acid transport to optimize offspring fitness, whereas catabolic signals reduce placental amino acid transport in an attempt to ensure survival and long-term reproductive capacity of the mother when resources are scarce. These signals regulate placental amino acid transport by controlling transcription, translation, plasma membrane trafficking, and degradation of transporters. Adaptations in placental amino acid transport capacity may underlie either under- or overgrowth of the fetus when maternal nutrient and hormone levels are altered as a result of altered maternal nutrition or metabolic disease. Strategies to modulate placental amino acid transport may prove effective to normalize fetal growth in intrauterine growth restriction and fetal overgrowth.
STUDY QUESTION
Does polycystic ovary syndrome (PCOS) in women without pregnancy complications affect placental signal transducer and activator of transcription 3 (STAT3) and mechanistic target of ...rapamycin (mTOR) signaling?
SUMMARY ANSWER
Placental STAT3 signaling is activated but mTOR signaling is unaffected in PCOS.
WHAT IS KNOWN ALREADY
Women with PCOS have increased risk of poor pregnancy outcomes (e.g. restricted or accelerated fetal growth), indicating placental dysfunction. Placental STAT3 and mTOR pathways regulate placental function and indirectly affect fetal growth.
STUDY DESIGN, SIZE, DURATION
In a case–control study, placental tissue and maternal blood were collected at delivery from 40 control pregnant women and 38 PCOS women with uncomplicated pregnancy.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women with PCOS were recruited at two medical centers and pregnant controls were recruited at one of these centers. Placental mRNA expression of genes encoding proteins related to steroid action, metabolic pathways and cytokines was analyzed by quantitative RT–PCR. Phosphorylated placental STAT3 (P-STAT3) and mTOR targets was measured by western blot. Levels of sex steroids in serum were determined by mass spectrometry.
MAIN RESULTS AND THE ROLE OF CHANCE
Placental P-STAT3 (Tyr-705) was increased in women with PCOS (P < 0.05) versus controls. Placental mTOR signaling was not affected in PCOS women when compared with controls. Circulating levels of androstenedione, androst-5-ene-3β, 17β-diol, testosterone, 5α-dihydrotestosterone and etiocholanolone glucuronide were higher and estradiol lower in women with PCOS than in controls (all P < 0.05). No correlation between sex steroid levels in serum and P-STAT3 was observed.
LIMITATIONS, REASONS FOR CAUTION
Women with PCOS and pregnancy complications were excluded to avoid the confounding effects of placental pathologies, which could modify STAT3 and mTOR signaling. Moreover, 97.4% of women with PCOS in the study displayed oligoamenorrhea at diagnosis. Thus, the current findings could be restricted to PCOS women with the oligo-anovulatory phenotype without pregnancy complications.
WIDER IMPLICATIONS OF THE FINDINGS
Phosphorylation of STAT3 is increased in the placenta from women with PCOS and uncomplicated pregnancies, indicating that specific metabolic placental pathways are activated in the absence of obstetric and perinatal complications.
STUDY FUNDING/COMPETING INTEREST(S)
The work was supported by the Swedish Medical Research Council (Project No. 2011-2732 and 2014-2775); Jane and Dan Olsson Foundation, Wilhelm and Martina Lundgrens's Science Fund; Hjalmar Svensson Foundation (E.S.-V and M.M.); Adlerbert Research Foundation; Swedish federal government under the LUA/ALF agreement ALFFGBG-136481 and 429501 and the Regional Research and Development agreement (VGFOUREG-5171, -11296 and -7861). MM thanks the Becas Chile Programme (Chile) and University of Chile for financial support through a postdoctoral fellowship. There are no competing interests.
Excess maternal glucocorticoids reduce placental amino acid transport and fetal growth, but whether these effects are mediated directly on the syncytiotrophoblast remains unknown. We hypothesised ...that glucocorticoids inhibit mechanistic target of rapamycin (mTOR) signaling and insulin-stimulated System A amino acid transport activity in primary human trophoblast (PHT) cells. Syncytialised PHTs, isolated from term placentas (n = 15), were treated with either cortisol (1 μM) or dexamethasone (1 μM), ± insulin (1 nM) for 24 h. Compared to vehicle, dexamethasone increased mRNA expression, but not protein abundance of the mTOR suppressor, regulated in development and DNA damage response 1 (REDD1). Dexamethasone enhanced insulin receptor abundance, activated mTOR complex 1 and 2 signaling and stimulated System A activity, measured by Na+-dependent 14C-methylaminoisobutyric acid uptake. Cortisol also activated mTORC1 without significantly altering insulin receptor or mTORC2 read-outs or System A activity. Both glucocorticoids downregulated expression of the glucocorticoid receptor and the System A transporter genes SLC38A1, SLC38A2 and SLC38A4, without altering SNAT1 or SNAT4 protein abundance. Neither cortisol nor dexamethasone affected System L amino acid transport. Insulin further enhanced mTOR and System A activity, irrespective of glucocorticoid treatment and despite downregulating its own receptor. Contrary to our hypothesis, glucocorticoids do not inhibit mTOR signaling or cause insulin resistance in cultured PHT cells. We speculate that glucocorticoids stimulate System A activity in PHT cells by activating mTOR signaling, which regulates amino acid transporters post-translationally. We conclude that downregulation of placental nutrient transport in vivo following excess maternal glucocorticoids is not mediated by a direct effect on the placenta.
Pregnant women with polycystic ovary syndrome (PCOS) are often overweight or obese. To study the effects of maternal androgen excess in obese dams on metabolism, placental function and fetal growth, ...female C57Bl6J mice were fed a control (CD) or a high fat/high sucrose (HF/HS) diet for 4-10 weeks, and then mated. On gestational day (GD) 15.5-17.5, dams were injected with dihydrotestosterone (CD-DHT, HF/HS-DHT) or a vehicle (CD-Veh, HF/HS-Veh). HF/HS dams had higher fat content, both before mating and on GD18.5, with no difference in glucose homeostasis, whereas the insulin sensitivity was higher in DHT-exposed dams. Compared to the CD groups, the livers from HF/HS dams weighed more on GD18.5, the triglyceride content was higher, and there was a dysregulation of liver enzymes related to lipogenesis and higher mRNA expression of Fitm1. Fetuses from HF/HS-Veh dams had lower liver triglyceride content and mRNA expression of Srebf1c. Maternal DHT exposure, regardless of diet, decreased fetal liver Pparg mRNA expression and increased placental androgen receptor protein expression. Maternal diet-induced obesity, together with androgen excess, affects maternal and fetal liver function as demonstrated by increased triglyceride content and dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage.
Abstract Fetal growth is primarily determined by nutrient availability, which is intimately related to placental nutrient transport. Detailed information on the regulation of placental nutrient ...transporters is therefore critical in order to understand the mechanisms underlying altered fetal growth and fetal programming. After briefly summarizing the cellular mechanisms for placental transport of glucose, amino acids and free fatty acids, we will discuss factors shown to regulate placental nutrient transporters and review the data describing how these factors are altered in pregnancy complications associated with abnormal fetal growth. We propose an integrated model of regulation of placental nutrient transport by maternal and placental factors in IUGR.
A large volume of food is being wasted every year, while the pulp and paper industry also generate a large amount of solid wastes on a daily basis, causing environmental challenges around the world. ...Dry anaerobic digestion (AD) of these solid wastes is a cost-effective method for proper management. However, dry digestion of these waste streams has been restricted due to their complex structure, the presence of possible inhibitors and inappropriate operating conditions. In light of this fact, dry digestion of food waste (FW) and paper wastes (PW) was conducted at different total solid (TS) concentrations of reactor mixtures of 14%, 16%, 18% and 20% TS, corresponding to substrate to inoculum (S/I) ratio of 0.5 and 1; investigating the optimum operating conditions for effective dry digestion of these complex wastes. The highest methane yields of 402 NmlCH4/gVS and 229 NmlCH4/gVS were obtained from digestion of FW and PW, respectively at 14%TS corresponding to an S/I ratio of 0.5. Increasing the S/I ratio from 0.5 to 1 and thereby having a TS content of 20% in the reactor mixtures was unfavorable to the digestion of both substrates.
Triglyceride (TG) hydrolases in the placental microvillous plasma membrane (MVM) release fatty acids from circulating lipoproteins and represent the critical initial step in transplacental fatty acid ...transfer. We investigated the activity of two TG hydrolases in MVM isolated from placentas of appropriately grown for gestational age pregnancies and pregnancies complicated by intrauterine growth restriction (IUGR), insulin-dependent diabetes mellitus (IDDM) or gestational diabetes mellitus (GDM). In addition, we measured protein expression of lipoprotein lipase (LPL) in MVM and two fatty acid binding proteins (L- and C-FABP) in placental homogenates. The TG hydrolase activities were assessed by measuring hydrolysis of 3H-trioleic acid incorporated into intralipid micelles after incubation with MVM. The placenta-specific TG hydrolase activity (optimum at pH 6) did not differ in the patient groups studied. MVM LPL activity (optimum at pH 8) was reduced by 47% in preterm IUGR (n = 8, P < 0.05), compared with gestational age-matched controls. The LPL activity in placentas of IDDM pregnancies was increased by 39% (n = 8, P < 0.05), compared with controls. No significant differences were observed in cases of GDM. We found no alteration in protein expression of LPL or C-FABP. The expression of L-FABP was increased by 112% (n = 8, P < 0.05) in IDDM and 64% (n = 8, P < 0.05) in GDM. These results indicate that alterations in MVM LPL activity and expression of L-FABP may contribute to the altered lipid deposition and metabolism in IUGR and diabetic pregnancies.
Women with polycystic ovary syndrome (PCOS) have elevated circulating androgens during pregnancy and are at an increased risk of adverse pregnancy outcomes. Here we tested the hypotheses that ...maternal androgen excess decrease placental and fetal growth, and placental expression of markers of steroidogenesis, angiogenesis and sympathetic activity, and that acupuncture with low-frequency electrical stimulation prevents these changes. Pregnant rats were exposed to vehicle or testosterone on gestational day (GD)15-19. Low-frequency electroacupuncture (EA) or handling, as a control for the EA procedure, was given to control or testosterone exposed dams on GD16-20. On GD21, blood pressure was measured and maternal blood, fetuses and placentas collected. Placental steroid receptor expression and proteins involved in angiogenic, neurotrophic and adrenergic signaling were analyzed.
EA did not affect any variables in control rats except maternal serum corticosterone, which was reduced. EA in testosterone exposed dams compared with controls increased systolic pressure by 30%, decreased circulating norepinephrine and corticosterone, fetal and placental weight and placental VEGFR1 and proNGF protein expression, and increased the VEGFA/VEGFR1 ratio, mature NGF (mNGF) and the mNGF/proNGF ratio.
In conclusion, low-frequency EA in control animals did not have any negative influence on any of the studied variables. In contrast, EA in pregnant dams exposed to testosterone increased blood pressure and impaired placental growth and function, leading to decreased fetal growth.
•Prenatal androgenization (PNA) negatively affect placental and fetal growth.•Electroacupuncture (EA) increases blood pressure in pregnant dams exposed to testosterone.•EA impairs placental function, leading to fetal growth restriction (FGR).•EA alters markers of sympathetic activity in placenta from PNA model.•There is a link between androgens, high blood pressure and FGR.
The aim of the present paper is to evaluate the use of linear and quadratic approximating response surfaces as metamodels in a reliability assessment of a sheet metal forming process using the Monte ...Carlo simulation technique. Monte Carlo simulation was used to determine the probability for springback and thickness variation in a sheet metal part. The conclusions of this study is that Monte Carlo analysis can be used to identify the most important variables and to estimate the range of the studied responses. Linear metamodels can be used to identify the important variables and to give an estimate of the probabilistic response. But quadratic surfaces are required for a more accurate analysis.
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