Maternal Plasma Triglycerides Research Articles

Maternal Plasma Lipids During Pregnancy, Insulin-like Growth Factor-1, and Excess Fetal Growth.

Maternal lipids during pregnancy and placental growth factors are associated with excess fetal growth. However, how these factors interact to increase the risk of delivering large-for-gestational-age (LGA) neonates remains unclear. In this study, we investigated the relationship between maternal plasma triglycerides (TGs) and free fatty acids (FFAs) during pregnancy, cord blood insulin-like growth factors (IGF), and LGA. In a cell model, we studied the effect of different FAs on placental IGF-1 secretion. This cohort study included pregnant women with term pregnancy and without diabetes or hypertensive disorders in pregnancy. Maternal fasting plasma TGs and FFAs were measured in the second trimester. Cord blood IGF-1, IGF-2, and IGF binding protein-1 and protein-3 were measured at the time of delivery. A human trophoblast cell line, 3A-sub-E, was used to evaluate the effect of different FFAs on placental IGF-1 secretion. We recruited 598 pregnant women-neonate pairs. Maternal plasma TG (180 mg/dL [152.5-185.5 mg/dL] vs 166 mg/dL [133-206 mg/dL], P = .04) and cord blood IGF-1 concentrations (72.7 ± 23.0 vs 54.1 ± 22.8 ng/mL, P < .001) were higher in the LGA group and were significantly associated with birth weight z score. Maternal plasma free palmitic acid (PA) and stearic acid (SA), but not oleic acid (OA) or linoleic acid (LA), were significantly associated with cord blood IGF-1 concentrations. In 3A-sub-E cells, treatment with PA, SA, and LA, but not OA, induced IGF-1 expression and secretion. Certain FFAs can induce placental IGF-1 secretion, which suggests a potential pathophysiology linking maternal plasma lipids and LGA.

Transferred maternal fatty acids stimulate fetal adipogenesis and lead to neonatal and adult obesity

The prevalence of adult and childhood obesity are increasing. Most of the human newborn’s body fat accumulates in the last half of intrauterine life. Fat in the fetus was thought to be mostly synthesized from glucose, but now it is commonly accepted that the bulk of it is the product of placental transfer of maternal fatty acids. Transported fatty acids originate in maternal plasma “free” fatty acids, fatty acids hydrolyzed from maternal plasma triglycerides, and the poly-unsaturated fatty acid component of maternal phospholipids. Glucose remains an important precursor of alpha-glycerol phosphate, to which most transported fatty acids are eventually esterified. Maternal plasma lipids are elevated in late pregnancy and even more in obese and diabetic pregnant women. This accelerates the placental transport of fatty acids. The hypothesis presented in this paper rests on the observations that the exponential increase in fat tissue in the human embryo’s body occurs in time to parallel the increase of lipids in the mother’s blood and depends on the chemical affinity of the transcription factor PPAR gamma to fatty acids and on fatty acid stimulation of adipocyte generation from precursor cells. The hypothesis asserts that transported maternal fatty acids activate the transcription factors in the fetus and initiate conversion of the mesenchymal stem cells into adipocytes. In obese and diabetic mothers, the higher plasma lipids facilitate increased placental fatty acid transfer. This will increase adipocyte generation and, through this, the prevalence of babies with increased fat cell size and number. Babies born with increased adipose tissue cellularity will have greater probability of growing up to become obese adolescents and adults. These newborns, whose obesity is hyperplastic as well as hypertrophic, as adults will have difficulty losing weight through diet and exercise or will regain the lost weight more quickly than others without these characteristics. Accordingly, increased placental fatty acid transfer and accelerated adipocyte generation may explain not only neonatal obesity, but some aspects of the adult obesity epidemic also. It is therefore recommended that prevention of fetal fat cell hyperplasia, by lowering maternal plasma lipids in mid and late pregnancy, should be attempted in pregnancies at risk for macrosomia.

Effects of maternal western-style diet on amniotic fluid volume and amnion VEGF profiles in a nonhuman primate model.

During pregnancy, high fat diet (HFD) induces maternal obesity, insulin resistance, and placental inflammatory responses that compromise placental and fetal development. Whether maternal HFD would adversely affect amniotic fluid volume (AFV) has not been explored. Vascular endothelial growth factor (VEGF) is expressed in the amnion and has been proposed as a regulator of AFV. Our aim was to investigate the effects of HFD on AFV and the associated changes in VEGF and soluble VEGF receptor 1 (sFlt‐1) expression profiles in three amnion regions of a nonhuman primate model. Further, we examined the relationships between VEGF expression and HFD‐induced changes in maternal metabolic status. Japanese macaques were maintained on control or HFD and amniotic fluid index (AFI) was measured as an ultrasonic estimate of AFV. Amniotic fluid VEGF concentrations were determined by ELISA and amnion VEGF and sFlt‐1 mRNA levels by real‐time RT‐qPCR. HFD increased maternal plasma triglyceride while glucose levels were unchanged. Maternal weight gain was found in diet‐sensitive animals whereas amniotic fluid VEGF concentration was reduced in diet‐resistant animals. HFD did not alter AFI and there was no correlation between AFI and maternal weight or amniotic fluid VEGF concentrations. VEGF mRNA levels were lowest in secondary placental amnion while sFlt‐1 mRNA were lowest in the primary placental amnion. HFD did not affect amnion VEGF or sFlt‐1 mRNA expression. These findings suggest that although maternal HFD increased maternal weight in diet‐sensitive and reduced amniotic fluid VEGF concentrations in diet‐resistant phenotype, AFV as indicated by the AFI, was not significantly affected.

Plasma Triglyceride Concentrations during Pregnancy Are Associated with Fetal Hyperinsulinemia, Insulin Resistance, and Birth Weight Independent of Maternal Hyperglycemia and Insulin Resistance

Objective: Intra-uterine environment has a great influence on fetal glucose metabolism and growth. Unlike gestational diabetes, the effect of maternal lipid metabolism on fetal glucose metabolism remains unknown. In this study, we evaluate the relationship between maternal plasma triglyceride concentrations during pregnancy, cord blood c-peptide, fetal insulin resistance index and birth weight. Research Design and Methods: 663 pregnant women who delivered singleton at National Taiwan University Hospital from 2013 to 2017 were enrolled in this cohort study. We measured plasma lipid profile at each trimester, cord blood c-peptide concentrations and birth weight. Fetal insulin resistance was measured by homeostatic model assessment 2-insulin resistance index (HOMA2-IR). Results: Maternal plasma triglyceride, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol increased significantly during pregnancy (all p&amp;lt;0.05). Maternal plasma triglyceride at the visit for oral glucose tolerance tests (OGTT) was associated with cord blood c-peptide (adjusted p&amp;lt;0.05) and fetal HOMA2-IR (adjusted p&amp;lt;0.05), adjusted for family history of diabetes, history of gestational diabetes, pre-pregnancy body mass index (BMI), gestational age, gestational weight gain, maternal hemoglobin A1c, maternal HOMA2-IR and cord blood glucose. Maternal plasma triglyceride at delivery was significantly associated with birth weight (adjusted p&amp;lt;0.05), adjusted for family history of diabetes, history of gestational diabetes, pre-pregnancy BMI, gestational age, gestational weight gain and maternal hemoglobin A1c. Similar associations were also found in women without gestational diabetes. Conclusions Maternal plasma triglyceride concentrations during pregnancy are associated with fetal hyperinsulinemia, insulin resistance and birth weight. Disclosure K. Chen: None. H. Li: None.

Determinants of Maternal Triglycerides in Women With Gestational Diabetes Mellitus in the Metformin in Gestational Diabetes (MiG) Study

OBJECTIVEFactors associated with increasing maternal triglyceride concentrations in late pregnancy include gestational age, obesity, preeclampsia, and altered glucose metabolism. In a subgroup of women in the Metformin in Gestational Diabetes (MiG) trial, maternal plasma triglycerides increased more between enrollment (30 weeks) and 36 weeks in those treated with metformin compared with insulin. The aim of this study was to explain this finding by examining factors potentially related to triglycerides in these women.RESEARCH DESIGN AND METHODSOf the 733 women randomized to metformin or insulin in the MiG trial, 432 (219 metformin and 213 insulin) had fasting plasma triglycerides measured at enrollment and at 36 weeks. Factors associated with maternal triglycerides were assessed using general linear modeling.RESULTSMean plasma triglyceride concentrations were 2.43 (95% CI 2.35–2.51) mmol/L at enrollment. Triglycerides were higher at 36 weeks in women randomized to metformin (2.94 [2.80–3.08] mmol/L; +23.13% [18.72–27.53%]) than insulin (2.65 [2.54–2.77] mmol/L, P = 0.002; +14.36% [10.91–17.82%], P = 0.002). At 36 weeks, triglycerides were associated with HbA1c (P = 0.03), ethnicity (P = 0.001), and treatment allocation (P = 0.005). In insulin-treated women, 36-week triglycerides were associated with 36-week HbA1c (P = 0.02), and in metformin-treated women, they were related to ethnicity.CONCLUSIONSAt 36 weeks, maternal triglycerides were related to glucose control in women treated with insulin and ethnicity in women treated with metformin. Whether there are ethnicity-related dietary changes or differences in metformin response that alter the relationship between glucose control and triglycerides requires further study.

Relationship of Maternal Malnutrition Caused by Di(2-ethylhexyl) Phthalate Exposure with Lifestyle Disease in Offspring

The hypothesis that offspring growing up malnourished during their fetal period have a high risk of lifestyle diseases in later life has been attracting great attention. Although animal experiments and epidemiological studies have been reported, most of them focused on the deficiency of maternal malnutritional elements or starvation. We found that di(2-ethylhexyl) phthalate (DEHP) decreased maternal plasma triglyceride levels, which is a significant source of nutrients for fetuses, in mice. Therefore, we analyzed how offspring exposed to malnutritional status during their fetal period develop potential adverse effects in later life. Male and female wild-type (mPPARα), Pparα-null, and hPPARα mice were treated with diets containing 0 or 0.05% DEHP. After 4 weeks, males and females in the same genotype and dose group were mated. After continued exposure until weaning, each group was divided into two groups, and one of them was dissected. The remaining was further divided into two subgroups; one was fed normal feed (control-diet group), while the other was fed a high-fat diet (HFD group). After 8-week feeding, all the mice were dissected. In the control-diet group, DEHP exposure at the fetal and pup stages increased food consumption in mPPARα and hPPARα mice, but not in Ppara-null mice. In contrast, DEHP exposure decreased plasma leptin levels in mPPARα and hPPARα mice at the weaning stage. In the HFD group, DEHP exposure at the fetal and pup stages influenced neither food consumption nor leptin levels. These findings suggest that maternal malnutrition may be caused by not only nutritional deficiency but also exposure to some chemicals such as DEHP, and the latter case may also influence feeding behavior in offspring. These effects may be related to hepatic PPARα and diminished by HFD feeding. Further study is warranted as to whether such feeding behavior influences the risk of lifestyle diseases such as obesity.

Impact of maternal dietary n-3 and n-6 fatty acids on milk medium-chain fatty acids and the implications for neonatal liver metabolism

Levels of n-6, n-3, and medium-chain fatty acids (MCFA) in milk are highly variable. Higher carbohydrate intakes are associated with increased mammary gland MCFA synthesis, but the role of unsaturated fatty acids for milk MCFA secretion is unclear. This study addressed whether n-6 and n-3 fatty acids, which are known to inhibit hepatic fatty acid synthesis, influence MCFA in rat and human milk and the implications of varying MCFA, n-6, and n-3 fatty acids in rat milk for metabolic regulation in the neonatal liver. Rats were fed a low-fat diet or one of six higher-fat diets, varying in 16:0, 18:1n-9, 18:2n-6, 18:3n-3, and long-chain (LC) n-3 fatty acids. Higher maternal dietary 18:2n-6 or 18:3n-3 did not influence milk MCFA, but lower maternal plasma triglycerides, due to either a low-fat or a high-fat high-LC n-3 diet led to higher milk MCFA. MCFA levels were inversely associated with 18:1n-9, 18:2n-6, and 18:3n-3 in human milk, likely reflecting the association between dietary total fat and unsaturated fatty acids. High LC n-3 fatty acid in rat milk was associated with lower hepatic Pklr, Acly, Fasn, and Scd1 and higher Hmgcs2 in the milk-fed rat neonate, with no effect of milk 18:1n-9, 18:2n-6, or MCFA. These studies show that the dietary fatty acid composition does not impact MCFA secretion in milk, but the fatty acid composition of milk, particularly the LC n-3 fatty acid, is relevant to hepatic metabolic regulation in the milk-fed neonate.

Fetal erythrocyte membrane lipids modification: preliminary observation of an early sign of compromised insulin sensitivity in offspring of gestational diabetic women

Intrauterine exposure to diabetes is a significant determinant of the development of obesity and early onset of Type 2 diabetes mellitus in the offspring. Both conditions are characterized by insulin resistance and the latter is associated with reduced membrane arachidonic and docosahexaenoic acids. Hence, we investigated if the membrane arachidonic and docosahexaenoic acids are depressed in the cord blood of babies born to women with gestational diabetes. Cord (fetal) and maternal blood were obtained at delivery from control subjects (n = 33) and women with gestational diabetes (n = 40) and analysed for plasma triglycerides and cholinephosphoglycerides, and erythrocyte choline- and ethanolaminephosphoglycerides fatty acids. Babies of gestational diabetic mothers had reduced docosahexaenoic acid in the plasma (5.9 +/- 1.4 vs. 7.1 +/- 2.0, P < 0.01) and erythrocyte (4.0 +/- 2.2 vs. 5.4 +/- 2.9, P < 0.05) cholinephosphoglycerides. Moreover, the total omega-6 and omega-3 fatty acids of the erythrocyte cholinephosphoglycerides were significantly lower (P < 0.05) in these babies. A similar trend was observed in plasma triglycerides and erythrocyte ethanolaminephosphoglycerides. The maternal plasma triglycerides and erythrocyte ethanolaminephosphoglycerides fatty acids profile were not different between the two groups. However, there was a reduction in arachidonic acid and total omega-6 fatty acids in the erythrocyte cholinephosphoglycerides of the gestational diabetic women. The altered plasma and erythrocyte fatty acids in the cord blood of babies born to women with gestational diabetes suggests a perturbation in the maternal-fetal nutrient transport and/or fetal lipid metabolism.

Essential Fatty Acids and Their Long-Chain Polyunsaturated Metabolites in Maternal and Cord Plasma Triglycerides during Late Gestation

The fatty acid composition of plasma lipids was determined in 41 pairs of mothers and their term infants at time of birth (38–42 postmenstrual weeks) by high-resolution capillary gas-liquid chromatography. Linoleic and α-linolenic acids were found at smaller concentrations in cord than in maternal triglycerides, in contrast to strikingly higher proportions of their long-chain polyunsaturated metabolites (LC-PUFA), which indicates a preferential maternofetal transport for certain physiologically important LC-PUFA. While no significant gestational age-dependent changes occurred in maternal plasma triglycerides, the values for most of the fetal long-chain n–3 metabolites increased with the duration of gestation, possibly reflecting an increased transplacental fatty acid passage during late pregnancy or a maturation of desaturation in the fetal liver.

Maternal-fetal fat transport versus new fat synthesis in the pregnant diabetic rat.

Rats were made diabetic by the injection of streptozotocin on day 12 of pregnancy and were investigated on days 17 and 20 of pregnancy. A significant correlation between both maternal plasma triglyceride and nonesterified fatty acid levels with placental or fetal triglyceride content was found, although fetal weight did not change significantly. In order to investigate the source of the placental and fetal fat the rats received, intragastrically 24 h earlier, 1-14C-triolein (as a preformed fatty acid tracer) and tritiated water (as a marker of de novo fatty acid synthesis). Several maternal tissues, placenta, and fetuses were extracted and analysed for fatty acid radioactivity. Compared with non-diabetic pregnant rats, maternal 14C-label storage was reduced. In contrast, the placental and fetal tissues demonstrated a significant rise in 14C-label, similar in magnitude to the rise in their triglyceride content. The pattern of 3H incorporation also indicated a pronounced decrease in maternal fatty acid synthesis, but no increase in de novo fatty acid synthesis in the fetus or placenta. The findings show that fetal lipids in the pregnant rat originate both from maternal fatty acids and those synthesized in situ. The diabetes-induced increment in fetal triglyceride content is derived, however, from preformed maternal triglycerides or non-esterified fatty acids secondary to the increase in their concentration in the maternal circulation.

Some effects of different dietary carbohydrates on pregnancy and lactation in rats.

Female rats were fed from weaning on diets with sucrose, starch, glucose or fructose as the carbohydrate source. Animals were killed at various stages throughout pregnancy and early lactation. Maternal plasma triglycerides (TG), cholesterol, free fatty acids, glucose, insulin and corticosteroids were measured. Lipogenic activity was assayed in the livers, adipose tissue and mammary tissue, and the results compared with those from non-pregnant rats. Insulin, corticosteroids and hepatic lipogenesis were also assayed in the embryos and in newborn pups. Dietary sucrose and fructose produced a significantly higher concentration of plasma TG in the non-pregnant, pregnant and lactating rats than did starch and glucose. All the diets led to an increase in TG concentration at the 20th day of pregnancy, which returned to the original concentration 2 days post-partum. The hypertriglyceridaemia of late pregnancy was accentuated by the feeding of sucrose and fructose. Maternal concentrations of plasma glucose were significantly reduced towards the end of pregnancy in all dietary groups. The replacement of starch by sucrose, or of glucose by fructose, enhanced hepatic lipogenesis. Fructose but not sucrose depressed fat synthesis in the adipose tissue. Hepatic fatty acid synthetase activity was increased in late pregnancy on all diets except that with starch. Late pregnancy intensified hepatic lipogenesis in rats fed sucrose or fructose. The results are discussed in relation to the metabolic changes during pregnancy and to sucrose feeding.

Maternal and fetal plasma lipids in alloxan diabetic and nondiabetic rabbits fed a peanut oil-cholesterol diet

The levels of triglyceride, free and ester cholesterol, and phospholipids were studied in peanut oil-cholesterol diet fed nondiabetic and alloxan-diabetic pregnant rabbits and their fetuses. The relative percentage of fatty acid composition was also determined in the cholesterol ester, triglyceride, nonesterified fatty acid, and phospholipid fractions of the maternal and fetal plasma lipids. In pregnant rabbits fed a fat-cholesterol diet, alloxan diabetes caused an increase in maternal plasma triglycerides and a decrease in fetal plasma free cholesterol and triglyceride levels. Alloxan diabetes also caused increases in fetal cholesterol linoleate and nonesterified fatty acid linoleate which are probably due to altered placental transport. Other changes in fetal plasma fatty acids of the alloxan diabetic group were increased cholesterol oleate and phospholipid palmitate and decreased cholesterol palmitate. These changes are most likely due to altered fetal lipid metabolism; however, altered placental transport may play a role. No alterations in maternal plasma fatty acid composition were detected by this study.

Foetal and maternal plasma triglyceride and cholesterol levels in the rabbit after foetal hypophysectomy by decapitation in utero.

Lipid and cholesterol synthesis is very active in the foetal rabbit liver and large amounts of lipid appear in the foetal liver at term and disappear in the first few days of life (Dawkins, 1966). The possibility that lipid metabolism at this stage may be regulated by the foetal pituitary is suggested by the observation that human anencephalic foetuses, which have a hypoplastic pituitary, have an abnormally thick pannus of subcutaneous fat (Angevine, 1938). This view is supported by the reports that foetal hypophysectomy by decapitation in the rabbit produces an increase in total body fat (Jost & Picon, 1958), in liver fat (Beam, 1960) and in blood cholesterol (Bearn & Pilkington, 1963). This work has now been extended to include studies on blood triglyceride concentrations. The foetuses were decapitated on the 22nd day of gestation by the intra-amniotic method (Beam & Pilkington, 1963): The uterine wall is incised and