Fetal Lipid Metabolism Research Articles

Cord blood vitamin E and lipids in infants born small for gestational age.

elevated cord blood vitamin E concentrations may be associated with a higher risk of SGA and are positively correlated with lipid levels, suggesting a potential role for vitamin E in fetal lipid metabolism. • Vitamin E is associated with the regulation of lipid metabolism. • Vitamin E is inversely related to birth weight. • Elevated cord blood vitamin E concentrations may be associated with a higher risk of SGA and positively correlated with lipid levels.

Transcriptome analysis reveals hepatic disordered lipid metabolism, lipotoxic injury, and abnormal development in IUGR sheep fetuses due to maternal undernutrition during late pregnancy

Although lipid metabolism in fetal livers under intrauterine growth restriction (IUGR) conditions has been widely studied, the implications of maternal undernutrition on fetal hepatic lipid metabolism, lipotoxic injury, and abnormal development remain largely unknown. Therefore, this study investigated the effects of maternal undernutrition on disordered hepatic lipid metabolism, lipotoxic injury, and abnormal development in IUGR sheep fetuses using transcriptome analysis. Seventeen singleton ewes were randomly divided into three groups on day 90 of pregnancy: a control group (CG; 0.63 MJ metabolic energy/body weight (ME/BW)0.75/day, n = 5), maternal undernutrition group 1 (MU1; 0.33 MJ ME/BW0.75/day, n = 6), and maternal undernutrition group 2 (MU2; 0.20 MJ ME/BW0.75/day, n = 6). The fetuses were euthanized and recovered on day 130 of pregnancy. The levels of free fatty acids (FFA) in maternal blood (P < 0.01), fetal blood (P < 0.01), and fetal livers (P < 0.05) were increased in the MU1 and MU2 groups, but fetal hepatic triglyceride (TG) levels in the MU2 group (P < 0.01) and β-hydroxybutyrate levels in the MU1 and MU2 groups (P < 0.01) were decreased compared to the CG. Severe inflammatory cell infiltration and increased non-alcoholic fatty liver disease activity scores were observed in MU1 and MU2 fetuses (P < 0.01). Progressive deposition of fetal hepatic reticular fibers and collagen fibers in the fetal livers of the MU1 and MU2 groups and significant hepatic fibrosis were observed in the MU2 fetuses (P < 0.05). Gene set enrichment analysis showed that genes involved in lipid accumulation and FFA beta oxidation were downregulated in both MU groups compared to those in the controls. The fetal liver mRNA expression of the β-oxidation regulator, acetyl-CoA acetyltransferase 1, and the TCA regulator, isocitrate dehydrogenase were reduced in MU1 (P < 0.05) and MU2 (P < 0.01) fetuses, and downregulated mRNA expression of long chain fatty acid CoA ligase 1 (P < 0.05) and glycerol-3-phosphate acyltransferase (P < 0.01) was observed in MU2 fetuses. Differentially expressed genes (DEGs) in MU1 versus CG (360 DEGs) and MU2 versus CG (746 DEGs) were identified using RNA sequencing. Bioinformatics analyses of the 231 intersecting DEGs between MU1 versus CG and MU2 versus CG indicated that neutrophil extracellular traps (NETs) were induced and played a central role in fetal hepatic injury in IUGR sheep. Increased maternal blood myeloperoxidase (MPO) levels (P < 0.01), NE (Elane)-positive areas in fetal liver sections (P < 0.05), and fetal liver MPO protein expression (P < 0.01) were found in the MU1 and MU2 groups; however, MPO levels were reduced in the fetal membrane (P < 0.01) and fetal blood (P < 0.05) in the MU1 group, and in the maternal-fetal placenta and fetal blood in the MU2 group (P < 0.01). Analysis of gene expression trends in the intersecting DEGs between MU1 versus CG (129 DEGs) and MU2 versus CG (515 DEGs) further revealed that 30 hub genes were essential regulators of the G2/M cell cycle, all of which were associated with hepatocellular carcinoma. G0/G1 phase cells of the fetal liver were reduced in the MU1 (P < 0.05) and MU2 (P < 0.01) groups, whereas G2/M phase cells were elevated in the MU1 and MU2 groups (P < 0.01). The representatives of upregulated hub genes and fetal liver protein expression of maternal embryonic leucine zipper kinase and protein regulator of cytokinesis 1 were progressively enhanced in the MU1 and MU2 groups (P < 0.01), and topoisomerase II alpha protein expression in the MU2 group (P < 0.05), as expected. These results indicate that FFA overload, severe lipotoxic injury, and NETs were induced, and disease-promoting regulators of the G2/M cell cycle were upregulated in the fetal liver of IUGR sheep. These findings provide new insights into the pathogenesis of impaired hepatic lipid metabolism and abnormal development and the molecular origin of post-natal liver disease in IUGR due to maternal undernutrition. This information can support the development of new therapeutic strategies.

Cord blood fatty acid binding protein 4 and lipids in infants born small- or large-for-gestational-age.

Adverse (poor or excessive) fetal growth "programs" an elevated risk of type 2 diabetes. Fatty acid binding protein 4 (FABP4) has been implicated in regulating insulin sensitivity and lipid metabolism relevant to fetal growth. We sought to determine whether FABP4 is associated with poor or excessive fetal growth and fetal lipids. In a nested case-control study in the Shanghai Birth Cohort including 60 trios of small-for-gestational-age (SGA, an indicator of poor fetal growth), large-for-gestational-age (LGA, an indicator of excessive fetal growth) and optimal-for-gestational-age (OGA, control) infants, we measured cord blood concentrations of FABP4 and lipids [high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols, triglycerides (TG)]. Adjusting for maternal and neonatal characteristics, higher cord blood FABP4 concentrations were associated with a lower odds of SGA [OR = 0.29 (0.11-0.77) per log unit increment in FABP4, P = 0.01], but were not associated with LGA (P = 0.46). Cord blood FABP4 was positively correlated with both LDL (r = 0.29, P = 0.025) and HDL (r = 0.33, P = 0.01) in LGA infants only. FABP4 was inversely associated with the risk of SGA. The study is the first to demonstrate LGA-specific positive correlations of cord blood FABP4 with HDL and LDL cholesterols, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth.

A bibliometric analysis of global research on vitamin D and reproductive health between 2012 and 2021: Learning from the past, planning for the future.

BackgroundVitamin D plays an invaluable role in reproductive health, but vitamin D insufficiency and deficiency are generally common among couples of childbearing age and pregnant women. This study aimed to evaluate the evolution, development trend, and research hotspot of publications on vitamin D and reproductive health.MethodsThe literature on vitamin D and reproductive health between 2012 and 2021 was retrieved from the Web of Science Core Collection (WoSCC). We used VOSviewer and CiteSpace to analyze publication years, countries, institutions, journals, highly cited authors and publications, and co-occurrence and citation bursts of keywords.ResultsA total of 1,828 articles and reviews on vitamin D and reproductive health published between 2012 and 2021 were identified. The annual publication outputs showed steady growth, with the most publications (272) and citations (7,097) in 2021. The United States contributed the most publications (458) and had the highest h-index (58). In terms of the number of publications and h-index, the journal named Nutrients ranked first. Nutrition dietetics, obstetrics gynecology, and endocrinology metabolism were three well-represented disciplines in research on vitamin D and reproductive health. Hollis BW, Wagner CL, and Litonjua AA were the top three most productive authors in this field during the last decade. Apart from vitamin D, the five keywords with the most frequent occurrence were vitamin D deficiency, pregnancy, risk, vitamin D supplementation, and 25-hydroxyvitamin D. Keyword citation burst analysis revealed that low birth weight, adipose tissue, marker, and embryo had a citation burst lasting until 2021.ConclusionIn conclusion, vitamin D has received continuous attention in the field of reproductive health, and there appears to have a higher level of research in North America. Multidisciplinary intersection contributed to the in-depth exploration in this field. And the effect of maternal vitamin D levels on fetal lipid metabolism and the prediction of fertility by vitamin D-related markers might be hotspots for the research.

Maternal polyunsaturated fatty acid concentrations during pregnancy and childhood liver fat accumulation

Maternal polyunsaturated fatty acids (PUFA) concentrations in pregnancy are essential for fetal lipid metabolism and adipocyte differentiation. Whether suboptimal maternal gestational PUFA concentrations adversely affect offspring liver fat development is unknown. We aimed to examine the associations of maternal n-3 and n-6 PUFA concentrations in pregnancy with childhood liver fat accumulation. In a population-based prospective cohort study among 2424 mother-child pairs, we measured maternal total and individual n-3 and n-6 PUFA plasma concentrations at mean gestational age of 20.6±1.1 weeks. Childhood liver fat fraction was obtained by MRI at 10 years. Non-alcoholic fatty liver disease was a liver fat fraction ≥5.0%. We observed that 1-Standard deviation (SD) higher maternal n-3 PUFA concentrations, especially DHA, was associated with a lower childhood liver fat fraction [-0.07 SD-score (95% CI-0.11 to -0.02, p-value=0.001) for both total n-3 PUFA and DHA concentrations]. Of n-6 PUFAs, 1-SD higher maternal dihomo-gamma-linolenic acid concentrations was associated with a higher childhood liver fat fraction [0.06 SD-score (95% CI 0.02-0.10, p-value=0.004)]. Associations were not explained by maternal or childhood socio-demographic and lifestyle characteristics. Associations were stronger among boys and less consistent among girls. Among boys, higher maternal total n-3 PUFA concentrations were associated with a lower risk of childhood non-alcohol fatty liver disease [odds ratio 0.42 (95% CI 0.25-0.70, p-value=0.001)]. Maternal lower n-3 PUFA and higher n-6 PUFA concentrations in pregnancy are associated with offspring liver fat accumulation in childhood. Optimizing maternal PUFA concentrations during pregnancy may be a target for preventing liver fat accumulation in their offspring.

Prenatal Exposure to BPA: The Effects on Hepatic Lipid Metabolism in Male and Female Rat Fetuses.

Bisphenol A (BPA) is an organic chemical compound widely used for manufacturing plastics. BPA exposure originates principally from the diet, but it can also originate from dermal contact. In over 90% of individuals, including pregnant women, BPA is detectable in several body fluids. The effects of this exposure on the fetus are under active investigation in several research laboratories. The aim of our work was to study the impact of prenatal exposure to BPA in the liver of rat fetuses from a sex-dependent point of view. We particularly investigated the effects of prenatal BPA exposure on hepatic lipids because of their crucial role, not only for the liver, but also for the whole-body functions. Our results demonstrate that the liver of rat fetuses, in utero exposed to a very low dose of BPA (2.5 µg/kg/day), displays significant modulations with regard to proteins involved in cholesterol and fatty acid biosynthesis and trafficking. Moreover, an impact on inflammatory process has been observed. All these effects are dependent on sex, being observable only in female rat fetuses. In conclusion, this work demonstrates that maternal exposure to BPA compromises hepatic lipid metabolism in female offspring, and it also reveals the perspective impact of BPA on human health at doses currently considered safe.

Gestational hypercholesterolemia alters fetal hepatic lipid metabolism and microRNA expression in Apo-E-deficient mice.

Maternal hypercholesterolemia (MHC) is a pathological condition characterized by an exaggerated rise in maternal serum cholesterol during gestation, which can alter offspring hepatic lipid metabolism. However, the extent that these maladaptations occur during gestation and the molecular mechanisms involved remain unknown. MicoRNAs (miRNA) are small, noncoding RNAs that contribute to the development and progression of nonalcoholic fatty liver disease. Therefore, we sought to determine the degree to which in utero exposure to excessive cholesterol affects fetal hepatic lipid metabolism and miRNA expression. Twelve female apoE-/- mice were randomly assigned to two different chow-based diets throughout gestation: control (CON) or the CON diet with cholesterol (0.15%). MHC reduced maternal fecundity and reduced litter size and weight. On gestational day 18, fetuses from MHC dams possessed increased placental cholesterol and hepatic triglycerides (TG), which were accompanied by a downregulation in the expression of hepatic lipogenic and TG synthesis and transport genes. Furthermore, fetal livers from MHC mothers showed increased miRNA-27a and reduced miRNA-200c expression. In summary, in utero exposure to MHC alters fetal lipid metabolism and lends mechanistic insight that implicates early changes in miRNA expression that may link to later-life programming of disease risk.

Maternal undernutrition induces fetal hepatic lipid metabolism disorder and affects the development of fetal liver in a sheep model.

Undernutrition accelerates body fat mobilization to alleviate negative energy balance, which disrupts homeostasis of lipid metabolism in maternal liver. However, little is known about its effect on fetal metabolism and development. Here, a sheep model was used to explore whether maternal undernutrition induces fetal lipid metabolism disorder and further inhibits fetal hepatic development. Twenty pregnant ewes were either fed normally or restricted to 30% level for 15 d, after which fetal hepatic samples were collected to conduct transcriptome, metabolome, histomorphology, and biochemical analysis. Results showed that maternal undernutrition altered the general transcriptome profile and metabolic mode in fetal liver. Fatty acid oxidation and ketogenesis were enhanced in fetal livers of undernourished ewes, which might be promoted by the activated peroxisome proliferator-activated receptor α signaling pathway, whereas cholesterol, steroid, and fatty acid synthesis were repressed. Maternal undernutrition increased triglyceride synthesis, decreased triglyceride degradation, and inhibited phospholipid degradation and synthesis in fetal liver. In addition, our data revealed that maternal undernutrition extremely inhibited DNA replication, cell cycle progression, and antiapoptosis and broke the balance between cell proliferation and apoptosis in fetal liver, indicating that maternal undernutrition affects the growth and development of fetal liver. Generally, these findings provide evidence that maternal undernutrition during pregnancy disturbs fetal lipid metabolism and inhibits fetal hepatic development in sheep, which greatly contribute to the further study of fetal metabolism and development in human beings.-Xue, Y., Guo, C., Hu, F., Zhu, W., Mao, S. Maternal undernutrition induces fetal hepatic lipid metabolism disorder and affects the development of fetal liver in a sheep model.

Altered maternal and placental lipid metabolism and fetal fat development in obesity: Current knowledge and advances in non-invasive assessment

Abnormal maternal lipid profiles, a hallmark of increased maternal adiposity, are associated with pregnancy complications such as preeclampsia and gestational diabetes, and offspring long-term metabolic health is impacted as the consequence of altered fetal growth, physiology and often iatrogenic prematurity. The metabolic changes associated with maternal obesity and/or the consumption of a high-fat diet effecting maternal lipid profiles and metabolism have also been documented to specifically affect placental function and may underlie changes in fetal development and life course disease risk.The placenta plays a critical role in mediating nutritional signals between the fetus and the mother. As obesity rates in women of reproductive age continue to increase, it is becoming evident that inclusion of new technologies that allow for a better understanding of early changes in placental lipid transport and metabolism, non-invasively in maternal circulation, maternal tissues, placenta, fetal circulation and fetal tissues are needed to aid timely clinical diagnosis and treatment for obesity-associated diseases.This review describes pregnancy lipid homeostasis, with specific reference to changes arising from altered maternal body composition on placental and fetal lipid transport and metabolism. Current technologies for lipid assessments, such as metabolomics and lipidomics may be impacted by labour or mode of delivery and are only reflective of a single time point. This review further addresses how established and novel technologies for assessing lipids and their metabolism non-invasively and during the course of pregnancy may guide future research into the effect of maternal metabolic health on pregnancy outcome, placenta and fetus.

The effects of prenatal metformin on obesogenic diet-induced alterations in maternal and fetal fatty acid metabolism.

BackgroundMaternal obesity may program the fetus and increase the susceptibility of the offspring to adult diseases. Metformin crosses the placenta and has been associated with decreased inflammation and reversal of fatty liver in obese leptin-deficient mice. We investigated the effects of metformin on maternal and fetal lipid metabolism and hepatic inflammation using a rat model of diet-induced obesity during pregnancy.MethodsFemale Wistar rats (6–7 weeks old) were fed normal or high calorie diets for 5 weeks. After mating with normal-diet fed males, half of the high calorie-fed dams received metformin (300 mg/kg, daily); dams (8 per group) continued diets through gestational day 19. Maternal and fetal livers and fetal brains were analyzed for fatty acids and for fatty acid metabolism-related gene expression. Data were analyzed by ANOVA followed by Dunnett’s post hoc testing.ResultsWhen compared to control-lean maternal livers, obesogenic-diet-exposed maternal livers showed significantly higher saturated fatty acids (14:0 and 16:0) and monounsaturated fatty acids (16:1n7 and 18:1n9) and lower polyunsaturated (18:2n6 and 20:4n6 [arachidonic acid]) and anti-inflammatory n3 polyunsaturated fatty acids (18:3n3 and 22:6n3 [docosahexaenoic acid]) (p < 0.05). Metformin did not affect diet-induced changes in maternal livers. Fetal livers exposed to the high calorie diet showed significantly increased saturated fatty acids (18:0) and monounsaturated fatty acids (18:1n9 and 18:1n7) and decreased polyunsaturated fatty acids (18:2n6, 20:4n6 and 22:6n3) and anti-inflammatory n3 polyunsaturated fatty acids, along with increased gene expression of fatty acid metabolism markers (Fasn, D5d, D6d, Scd1, Lxrα). Metformin significantly attenuated diet-induced inflammation and 18:1n9 and 22:6n3 in fetal livers, as well as n3 fatty acids (p < 0.05). Prenatal obesogenic diet exposure significantly increased fetal liver IFNγ levels (p < 0.05), which was reversed by maternal metformin treatment (p < 0.05).ConclusionsConsumption of a high calorie diet significantly affected maternal and fetal fatty acid metabolism. It reduced anti-inflammatory polyunsaturated fatty acids in maternal and fetal livers, altered gene expression of fatty acid metabolism markers, and induced inflammation in the fetal livers. Prenatal metformin attenuated some diet-induced fatty acid changes and inflammation in the fetal livers without affecting maternal livers, suggesting that maternal metformin may impact fetal/neonatal fatty acid/lipid metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0115-9) contains supplementary material, which is available to authorized users.

Changes of Phospholipids in Fetal Liver of Mice Conceived by In Vitro Fertilization1

Environmental influences during early development increase the susceptibility to metabolism diseases in adulthood. Assisted reproductive techniques (ART) expose the gametes or preimplantation embryo to a nonphysiological environment that increases the risk of metabolism diseases in later life. However, the precise underlying causes of ART-related metabolism disease remain unclear. In our previous study, by using a mouse model, we found that ART resulted in placental maldevelopment and dysfunction that led to reduced fetal growth. The lipid metabolism and lipid transporters in the placenta were also affected by ART. Based on these findings, we hypothesized that ART may hamper fetal lipid metabolism, which could predispose to metabolic diseases in later life. In the present examination, by lipidomic analysis, we investigated for the first time the effect of ART on phospholipid profiles in the fetal liver in a mouse model and presented it in a detailed overview. We revealed that ART increased significantly the level of lysophosphatidylcholine (LPC), phosphatidic acid (PA), and lysophosphatidylethanolamine in the livers of fetuses compared with those in the controls. LPC and PA acts as signaling molecules involved in the majority of cellular processes regulating many crucial physiological and pathophysiological processes. LPC has been shown to play a crucial role in the development of atherosclerosis and type 2 diabetes, and an increase in PA can result in insulin resistance. We proposed that changes of LPC and PA may be one of the causes of the changes in glucose metabolism and vascular dysfunction in the mouse model of ART.

Impact of maternal undernutrition around the time of conception on factors regulating hepatic lipid metabolism and microRNAs in singleton and twin fetuses.

We have investigated the effects of embryo number and maternal undernutrition imposed either around the time of conception or before implantation on hepatic lipid metabolism in the sheep fetus. We have demonstrated that periconceptional undernutrition and preimplantation undernutrition each resulted in decreased hepatic fatty acid β-oxidation regulators, PGC-1α (P < 0.05), PDK2 (P < 0.01), and PDK4 (P < 0.01) mRNA expression in singleton and twin fetuses at 135-138 days gestation. In singletons, there was also lower hepatic PDK4 (P < 0.01), CPT-1 (P < 0.01), and PKCζ (P < 0.01) protein abundance in the PCUN and PIUN groups and a lower protein abundance of PDPK-1 (P < 0.05) in the PCUN group. Interestingly, in twins, the hepatic protein abundance of p-AMPK (Ser(485)) (P < 0.01), p-PDPK-1 (Ser(41)) (P < 0.05), and PKCζ (P < 0.05) was higher in the PCUN and PIUN groups, and hepatic PDK4 (P < 0.001) and CPT-1 (P < 0.05) protein abundance was also higher in the PIUN twin fetus. We also found that the expression of a number of microRNAs was altered in response to PCUN or PIUN and that there is evidence that these changes may underlie the changes in the protein abundance of key regulators of hepatic fatty acid β-oxidation in the PCUN and PIUN groups. Therefore, embryo number and the timing of maternal undernutrition in early pregnancy have a differential impact on hepatic microRNA expression and on the factors that regulate hepatic fatty acid oxidation and lipid synthesis.

Maternal and fetal lipid metabolism under normal and gestational diabetic conditions.

Maternal lipids are strong determinants of fetal fat mass. Here we review the overall lipid metabolism in normal and gestational diabetes mellitus (GDM) pregnancies. During early pregnancy, the increase in maternal fat depots is facilitated by insulin, followed by increased adipose tissue breakdown and subsequent hypertriglyceridemia, mainly as a result of insulin resistance (IR) and estrogen effects. The response to diabetes is variable as a result of greater IR but decreased estrogen levels. The vast majority of fatty acids (FAs) in the maternal circulation are esterified and associated with lipoproteins. These are taken up by the placenta and hydrolyzed by lipases. The released FAs enter various metabolic routes and are released into fetal circulation. Although these determinants are modified in maternal GDM, the fetus does not seem to receive more FAs than in non-GDM pregnancies. Long-chain polyunsaturated FAs are essential for fetal development and are obtained from the mother. Mitochondrial FA oxidation occurs in fetal tissue and in placenta and contributes to energy production. Fetal fat accretion during the last weeks of gestation occurs very rapidly and is sustained not only by FAs crossing the placenta, but also by fetal lipogenesis. Fetal hyperinsulinemia in GDM mothers promotes excess accretion of adipose tissue, which gives rise to altered adipocytokine profiles. Fetal lipoproteins are low at birth, but the GDM effects are unclear. The increase in body fat in neonates of GDM women is a risk factor for obesity in early childhood and later life.

Superovulation Induced Changes of Lipid Metabolism in Ovaries and Embryos and Its Probable Mechanism.

This research was intended to investigate the fetal origins of changed birth weight of the offspring born through assisted reproductive technology (ART). The association between hormone and lipid metabolism or body weight has been generally accepted, and as the basic and specific treatment in ART procedure, gonadotropin stimulation might have potential effects on intrauterine lipid metabolism. In our studies, the mice were superovulated with two doses of gonadotropin. The cholesterol metabolism in ovaries and the triglyceride metabolism in embryos were analyzed. The results showed gonadotropin probably accelerated luteinization and induced a longer time follicle development and ovulation, which resulted in histological and morphological alteration of ovary, and increased the cholesterol content and the expressions of steroidogenesis-related genes. In embryos, gonadotropin increased lipid accumulation and decreased fatty acid synthesis in a dose-dependent manner. Moreover, the changes of fatty acid composition were also shown in superovulation groups. Our studies firstly provided the evidence that the superovulation might affect the maternal and fetal lipid metabolism. These variations of lipid metabolism in our results may be associated with birth weight of ART infants.

Supplementation of Maternal Diets with Choline, B‐vitamin and Docosahexaenoic Acid (DHA) Alters Gene Expressions Associated with Hepatic Lipid Metabolism in Offspring

This study was to explore whether maternal supplementation of choline with supporting b-vitamins and DHA during malnourishment influences fetal expression of RNAs involved in hepatic lipid metabolism. Pregnant gilts (n=24) were randomly assigned to full-fed control (no feed intake restriction) or global nutrient restricted (GNR, 50-70% feed intake restriction) groups. The GNR gilts received supplementation of choline and supporting b-vitamins and/or DHA according to a 2 x 2 factorial arrangement. Piglets were delivered by C-section on d 110 ± 2 and fetal liver samples were collected. RNA was extracted, and miRNA and mRNA libraries were constructed and sequenced by using Ion Proton Sequencing Platform. Results showed that abundance of miR-21, miR-122, miR-145, miR-103, miR-221, miR490-3p and miR-375 associated with regulation of hepatic lipid metabolism were modified in offspring from GNR gilts as compared with offspring from control gilts. The modifications in these miRNAs were affected by maternal supplementation of choline or/and DHA. Additionally, the expressions of HMGCS2, FABP1, FABP2, AACS, CHKA, GPCPD1, LPCAT3, AGPAT6, SCD, ELOVL7, ELOVL6, PTGS1 and LRAT significantly differed between offspring from control and GNR gilts. Supplementation of choline or/and DHA modified gene expressions of PPARα, RXR2, HMGCS2, FABP2, SERBF2, CHKA, AGPAT6, SCD, ELOVL7, ELOVL6 and PTGS. These results strongly suggest that maternal choline and DHA play important roles in programming of fetal lipid metabolism during development via regulation of gene expression. Supported by Bill & Melinda Gates Foundation, GCE OPP1061037.

Hepatic steatosis is prevalent in stillborns delivered to women with diabetes mellitus.

Maternal diabetes is a risk factor for pregnancy complications, including stillbirth and macrosomia. Evolving data suggest that diabetes during pregnancy also has long-term consequences for offspring, putting them at risk for obesity and the metabolic syndrome in childhood. Because nonalcoholic fatty liver disease is known to occur in adults and children with insulin resistance, we hypothesized that altered lipid metabolism in fetuses of diabetic mothers may manifest with hepatic steatosis. We undertook a retrospective autopsy study to compare the presence and degree of hepatic steatosis between stillborns delivered to women with pregestational or gestational diabetes mellitus (gestational age 20-40 weeks; n = 33) and age-matched nondiabetic control stillbirth cases (n = 48), the latter enriched for maternal obesity, macrosomia, and similar cause of demise. Histopathologic hepatic steatosis was significantly more prevalent and severe in the diabetic subjects (26/33, 78.8%) than in the controls (8/48, 16.6%) (P < 0.001). Within the diabetic cohort, the severity of steatosis was related directly to gestational age, birth weight, and liver weight, with no correlation of presence or severity of steatosis in the control group to maternal or fetal factors, including maternal body mass index or fetal macrosomia. Although macrosomic stillborns were more common in diabetic women with %hemoglobin A1c >6 and body mass index >30 kg/m, fetal steatosis was independent of glycemic control, maternal obesity, type of diabetes, ethnicity, or fetal sex in our cohort. This study is the first to our knowledge to demonstrate a specific association between fetal hepatic steatosis and maternal diabetes.

Intrauterine Effects of Impaired Lipid Homeostasis in Pregnancy Diseases

Lipids are crucial structural and bioactive components that sustain embryo, fetal and placental development and growth. Intrauterine development can be disturbed by several diseases that impair maternal lipid homeostasis and lead to abnormal lipid concentrations in the fetal circulation. Deficiency in essential fatty acids can lead to congenital malformations and visual and cognitive problems in the newborn. Either deficient mother-to-fetus lipid transfer or abnormal maternal- fetal lipid metabolism can cause fetal growth restriction. On the other hand, excessive mother-to-fetus fatty acid transfer can induce fetal overgrowth and lipid overacummulation in different fetal organs and tissues. The placenta plays a fundamental role in the transfer of lipid moieties to the fetal compartment and is affected by maternal diseases associated with impaired lipid homeostasis. Postnatal consequences may be evident in the neonatal period or later in life. Indeed, both defects and excess of different lipid species can lead to the intrauterine programming of metabolic and cardiovascular diseases in the offspring. This review summarizes the lipid impairments induced by different pathologies, including placental insufficiency, malnutrition, obesity and diabetes, and their consequent developmental defects.

Fructose intake during pregnancy up-regulates the expression of maternal and fetal hepatic sterol regulatory element-binding protein-1c in rats

Excess fructose consumption is associated with the development of type 2 diabetes and obesity. However, the impact of fructose intake on maternal and fetal lipid metabolism during pregnancy is not known. The aim of this study was to examine whether maternal fructose intake during pregnancy would affect fetal and maternal hepatic lipid metabolism. Pregnant Wistar rats were randomly divided into untreated control and fructose-treated groups; the fructose-treated group received fructose via drinking water throughout pregnancy. On gestational day 20, glucose and insulin concentration in the maternal plasma were measured. The mRNA expression of sterol regulatory element-binding protein (SREBP)-1c and its target genes in the liver of dams and fetuses were analyzed by real-time PCR. Significantly higher maternal plasma glucose levels, indicating hyperglycemia, was observed in the fructose-treated group than in the control group. Furthermore, the fructose-treated group showed significantly higher expression levels of both maternal and fetal SREBP-1c mRNA and protein and significantly elevated expression of fatty acid synthase; the group also showed reduced acyl-CoA oxidase levels in the maternal liver. Thus, our results suggest that maternal fructose intake during pregnancy causes maternal hyperglycemia and up-regulates hepatic SREBP-1c expression in both fetuses and dams. This may lead to defects in carbohydrate and lipid metabolism in the adult offspring.

Cord blood triglycerides are associated with IGF-I levels and contribute to the identification of growth-restricted neonates

ObjectiveThe aim of this study was to investigate whether readily available laboratory tests may aid in the identification of growth-restricted neonates. DesignCord serum levels of 15 chemical analytes, including insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) were measured in newborns ≥36weeks gestational age (GA). Based on the number of anthropometric indices (out of four) with values ≤25th centile for GA, the babies were allocated into three groups, i.e., Group250, Group251 and Group252 corresponding to neonates with 0, 1 and 2 or more indices, respectively, that were ≤25th centile for GA. Furthermore, two composite variables were developed: A25 (Group250 and Group251) and B25 (Group250 and Group252). The data were evaluated by the Mann–Whitney test and multiple regression analyses. ResultsCord serum triglycerides and total cholesterol levels were significantly higher in Group252 compared to Group250 (p values 0.004 and 0.0009, respectively). The triglycerides almost doubled the power of the variable B25 for predicting IGF-I levels and were found to have a highly significant, negative association with the IGF-I levels (p<0.0001). The IGF-I along with the IGFBP-3 levels explained almost one third of the variation of triglycerides. ConclusionCord serum triglycerides can assist in the identification of growth-restricted neonates. The novel finding of the association of triglycerides with IGF-I calls for further research as this can illuminate unknown aspects of the fetal lipid metabolism.

183: Maternal obesity and evidence of fetal programming of lipid metabolism

programming of lipid metabolism Beth Plunkett, Gina Morgan, Richard Silver, Susan Crawford NorthShore University HealthSystem, Department of Obstetrics and Gynecology, Evanston, IL, NorthShore University HealthSystem, Surgery, Evanston, IL OBJECTIVE: To determine if pregestational maternal obesity alters fetal lipid metabolism in a leptin-deficient mouse model. STUDY DESIGN: Leptin-deficient mice (ob/ob) lack appetite control and become obese through overeating. Fetuses of LEAN ob/ob dams were compared to fetuses of OBESE ob/ob dams. LEAN ob/ob dams were treated with exogenous leptin after weaning to maintain normal body weight and fertility. The OBESE ob/ob dams were treated only with periconceptional leptin. Leptin treatments were stopped in both groups after post-conception D6.5. Dams were mated to C57Bl6 wildtype (WT) studs and sacrificed on D18. Fetal livers were harvested and RNA extracted for Affymetrix gene array analysis and Ingenuity Pathway Assessment. RESULTS: Preconceptional weight was significantly lower in the LEAN (n 4) than OBESE (n 5; 20.7 2.9 vs. 28.5 2.3g, P 0.05) as was D18 glucose (196.0 36.9 vs. 172.3 41.2 mg/dL, respectively, P 0.05) and D18 insulin (1.00 0.5 and1.14 1.0 ng/ml, respectively, P 0.05). Fetal livers (n 3) demonstrated significant changes in the expressions of 15 genes related to lipid metabolism in the fetuses of LEAN versus OBESE. CONCLUSION: In a leptin-deficient mouse model, maternal preconceptional obesity independently changes expression of multiple genes involved in fetal lipid metabolism. The identified genes modulate physiological processes associated with glucose intolerance and triglyceride metabolism. These findings suggest that significant metabolic disturbance related to maternal obesity may begin in fetal life. 184 Neonatal neurologic evaluation in a retinoic acid induced rat myelomeningocele model Brendan Grubbs, Shelley Hough, Samer Assaf, Lisa Korst, Martin Pera, Ramen Chmait University of Southern California, Obstetrics & Gynecology, Los Angeles, CA, University of Southern California, Eli & Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USC Keck School of Medicine, Obstetrics & Gynecology, Los Angeles, CA, University of Melbourne, Florey Neuroscience Institute, and the Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia OBJECTIVE: To evaluate the response to limb pinch in newborn rats with retinoic acid induced myelomeningocele. STUDY DESIGN: Pregnant (Day 10) Sprague-Dawley dams were gavage fed retinoic acid (60 mg/kg), as described by Danzer (Danzer E, et al. Experimental Neurology 2005; 194: 467-475), in order to generate open neural tube defects. Cesarean sections were performed on day 21.5, under isoflurane anesthesia, and forceps were used to lightly pinch a fore limb and a hind limb 3 times each. Withdrawal of the pinched limb each time, and full body squirm were considered positive reactions. To control for anesthesia and death prior to evaluation, only pups exhibiting a positive forelimb response were included in analysis. A 2-tailed Fisher’s exact test was used for analysis of the results. RESULTS: Of 44 rat fetuses exposed to retinoic acid, 40 (91%) developed a myelomeningocele. Ten of these pups were excluded for a negative forelimb pinch response. 26 of the 30 (86.7%) remaining pups with myelomeningoceles vs. 1 of 12 (8.3%) control pups exhibited a negative response to hind limb pinch, yielding an odds ratio of 71.5 (95% CI 6.1-1981.1, p 0.0001). CONCLUSION: Our findings verify the efficacy of the retinoic acid model, and demonstrate that rat pups affected by myelomeningocele were substantially more likely to exhibit a negative pinch response compared with control pups. Observation of the response to limb pinch in this model may be useful for evaluation following attempts at repair or regeneration of damaged neural tissue.