Impact of maternal undernutrition during the periconceptional period, fetal number, and fetal sex on the development of the hypothalamo-pituitary adrenal axis in sheep during late gestation

Evidence from epidemiologic, clinical, and experimental studies has shown that a suboptimal intrauterine environment during early pregnancy can alter fetal growth and gestation length and is associated with an increased prevalence of adult hypertension and cardiovascular disease. It has been postulated that maternal nutrient restriction may act to reprogram the development of the pituitary-adrenal axis, resulting in excess glucocorticoid exposure and adverse health outcomes in later life. It is unknown, however, whether maternal nutrient restriction during the periconceptional period alters the development of the fetal pituitary-adrenal axis or whether the effects of periconceptional undernutrition can be reversed by the provision of an adequate level of maternal nutrition throughout the remainder of pregnancy. We have investigated the effect of restricted periconceptional nutrition (70% of control feed allowance) from 60 days before until 7 days after mating and the effect of restricted gestational nutrition from Day 8 to 147 of gestation on the development of the fetal hypothalamo-pituitary adrenal (HPA) axis in the sheep. In these studies, we have also investigated the effects of fetal number and sex on the pituitary-adrenal responses to periconceptional and gestational undernutrition. In ewes maintained on a control diet throughout the periconceptional and gestational periods, fetal plasma ACTH concentrations were higher and the prepartum surge in cortisol occurred earlier in singletons compared with twins. Plasma ACTH concentrations were also significantly higher in male compared with female singletons, and in twin fetuses, the prepartum surge in cortisol concentrations occurred earlier in males than in females. Periconceptional undernutrition resulted in higher fetal plasma concentrations of ACTH between 110 and 145 days of gestation and a significantly greater cortisol response to a bolus dose of corticotropin-releasing hormone in twin, but not singleton, fetuses in late gestation. We have therefore demonstrated that fetal number and sex each has an impact on the timing of the prepartum activation of the HPA axis in the sheep. Restriction of the level of maternal nutrition before and in the first week of a twin pregnancy results in stimulation of the fetal pituitary-adrenal axis in late gestation, and this effect is not reversed by the provision of a maintenance control diet from the second week of pregnancy.     

Increased maternal fat consumption during pregnancy alters body composition in neonatal mice

Maternal overnutrition prior to and during gestation causes pronounced metabolic dysfunction in the adult offspring. However, less is known about metabolic adaptations in the offspring that occur independently of postnatal growth and nutrition. Therefore, we evaluated the impact of excess maternal dietary lipid intake on the in utero programming of body composition, hepatic function, and hypothalamic development in newborn (P0) offspring. Female mice were fed a low-fat (LF) or high-fat (HF) diet and were mated after 4, 12, and 23 wk. A subset of the obese HF dams was switched to the LF diet during the second (DR2) or third (DR3) pregnancies. The HF offspring accrued more fat mass than the LF pups, regardless of duration of maternal HF diet consumption or prepregnancy maternal adiposity. Increased neonatal adiposity was not observed in the DR3 pups. Liver weights were reduced in the HF offspring but not in the DR2 or DR3 pups. Offspring hepatic triglyceride content was reduced in the HF pups, but hepatic inflammation and expression of lipid metabolism genes were largely unaffected by maternal diet. Maternal diet did not alter the hypothalamic expression of orexigenic and anorexigenic neuropeptides in the offspring. Thus, the intrauterine programming of increased neonatal adiposity and reduced liver size by maternal overnutrition is evident in mice at birth and occurs prior to the development of maternal obesity. These observations demonstrate that dietary intervention during pregnancy minimizes the deleterious effects of maternal obesity on offspring body composition, potentially reducing the offsprings' risk of developing obesity and related diseases later in life.     

Nutritional manipulation of fetal adipose tissue deposition and uncoupling protein 1 messenger RNA abundance in the sheep: differential effects of timing and duration

A range of epidemiological and experimental studies have indicated that suboptimal nutrition at different stages of gestation is associated with an increased prevalence of adult hypertension, cardiovascular disease, and obesity. The timing of prenatal nutrient restriction is important in determining postnatal outcomes-including obesity. The present study, aimed to determine the extent to which fetal adiposity and expression of the key thermogenic protein, uncoupling protein (UCP)1, are altered by restriction of maternal nutrient intake imposed during four different periods, starting from before conception. Maternal nutrient intake was restricted from 60 days before until 8 days after mating (periconceptional nutrient restriction; R-C), from 60 days before mating and throughout gestation (R-R), from 8 days gestation until term (C-R), or from 115 days gestation until term. Fetal perirenal adipose tissue (PAT) was sampled near to term at approximately 143 days. UCP1 mRNA, but not protein, abundance in PAT was increased in fetuses in the R-R group (C-C 63 +/- 18; R-C 83 +/- 43; C-R 103 +/- 38; R-R 167 +/- 50 arbitrary units (P < 0.05)). In contrast, the abundance of UCP1 mRNA, but not protein, in fetal PAT was decreased when maternal nutrition was restricted from 115 days gestation. The major effect of maternal nutrient restriction on adipose tissue deposition occurred in the C-R group, in which the proportion of fetal fat was doubled, whereas maternal nutrient restriction from 115 days gestation reduced fetal fat deposition. In conclusion, there are differential effects of maternal and therefore fetal nutrient restriction on UCP1 mRNA expression and fetal fat mass and these effects are dependent on the timing and duration of nutrient restriction.     

Impact of periconceptional nutrition on maternal and fetal leptin and fetal adiposity in singleton and twin pregnancies

It has been proposed that maternal nutrient restriction may alter the functional development of the adipocyte and the synthesis and secretion of the adipocyte-derived hormone, leptin, before birth. We have investigated the effects of restricted periconceptional undernutrition and/or restricted gestational nutrition on fetal plasma leptin concentrations and fetal adiposity in late gestation. There was no effect of either restricted periconceptional or gestational nutrition on maternal or fetal plasma leptin concentrations in singleton or twin pregnancies during late gestation. In ewes carrying twins, but not singletons, maternal plasma leptin concentrations in late gestation were directly related to the change in ewe weight that occurred during the 60 days before mating [maternal leptin = 0.9 (change in ewe weight) + 7.8; r = 0.6, P < 0.05]. In twin, but not singleton, pregnancies, there was also a significant relationship between maternal and fetal leptin concentrations (maternal leptin = 0.5 fetal leptin + 4.2, r = 0.63, P < 0.005). The relative mass of perirenal fat was also significantly increased in twin fetal sheep in the control-restricted group (6.0 +/- 0.5) compared with the other nutritional groups (control-control: 4.1 +/- 0.4; restricted-restricted: 4.4 +/- 0.4; restricted-control: 4.3 +/- 0.3). In conclusion, the impact of maternal undernutrition on maternal plasma leptin concentrations during late gestation is dependent on fetal number. Furthermore, we have found that there is an increased fetal adiposity in the twins of ewes that experienced restricted nutrition throughout gestation, and this may be important in the programming of postnatal adiposity.     

Early hypothalamic FTO overexpression in response to maternal obesity--potential contribution to postweaning hyperphagia

Background

Intrauterine and postnatal overnutrition program hyperphagia, adiposity and glucose intolerance in offspring. Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene have been linked to increased risk of obesity. FTO is highly expressed in hypothalamic regions critical for energy balance and hyperphagic phenotypes were linked with FTO SNPs. As nutrition during fetal development can influence the expression of genes involved in metabolic function, we investigated the impact of maternal obesity on FTO.

Methods

Female Sprague Dawley rats were exposed to chow or high fat diet (HFD) for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1 (PND1), some litters were adjusted to 3 pups (vs. 12 control) to induce postnatal overnutrition. At PND20, rats were weaned onto chow or HFD for 15 weeks. FTO mRNA expression in the hypothalamus and liver, as well as hepatic markers of lipid metabolism were measured.

Results

At weaning, hypothalamic FTO mRNA expression was increased significantly in offspring of obese mothers and FTO was correlated with both visceral and epididymal fat mass (P<0.05); body weight approached significance (P = 0.07). Hepatic FTO and Fatty Acid Synthase mRNA expression were decreased by maternal obesity. At 18 weeks, FTO mRNA expression did not differ between groups; however body weight was significantly correlated with hypothalamic FTO. Postnatal HFD feeding significantly reduced hepatic Carnitine Palmitoyltransferase-1a but did not affect the expression of other hepatic markers investigated. FTO was not affected by chronic HFD feeding.

Significance

Maternal obesity significantly impacted FTO expression in both hypothalamus and liver at weaning. Early overexpression of hypothalamic FTO correlated with increased adiposity and later food intake of siblings exposed to HFD suggesting upregulation of FTO may contribute to subsequent hyperphagia, in line with some human data. No effect of maternal obesity was observed on FTO in adulthood.     

Peri-conceptional obesogenic exposure induces sex-specific programming of disease susceptibilities in adult mouse offspring

Vulnerability of the fetus upon maternal obesity can potentially occur during all developmental phases. We aimed at elaborating longer-term health outcomes of fetal overnutrition during the earliest stages of development. We utilized Naval Medical Research Institute (NMRI) mice to induce pre-conceptional and gestational obesity and followed offspring outcomes in the absence of any postnatal obesogenic influences. Male adult offspring developed overweight, insulin resistance, hyperleptinemia, hyperuricemia and hepatic steatosis; all these features were not observed in females. Instead, they showed impaired fasting glucose and a reduced fat mass and adipocyte size. Influences of the interaction of maternal diet 1 sex concerned offspring genes involved in fatty liver disease, lipid droplet size regulation and fat mass expansion. These data suggest that a peri-conceptional obesogenic exposure is sufficient to shape offspring gene expression patterns and health outcomes in a sex- and organ-specific manner, indicating varying developmental vulnerabilities between sexes towards metabolic disease in response to maternal overnutrition.     

The Influence of Overweight and Obesity on Longitudinal Trends in Maternal Serum Leptin Levels During Pregnancy

Maternal obesity influences a number of metabolic factors that can affect the course of pregnancy. Among these factors, leptin plays an important role in energy metabolism and fetal development during pregnancy. Our objective was to estimate the influence of maternal overweight/obesity on variation in the maternal serum leptin profile during pregnancy. In a prospective cohort of 143 adult gravidas with singleton pregnancies presenting for general prenatal care, we measured serum leptin levels at 6–10, 10–14, 16–20, 22–26, and 32–36 weeks' gestation. The longitudinal effects of maternal prepregnancy BMI, categorized as nonoverweight (≤26.0 kg/m²) and overweight/obese (>26.0 kg/m²), on serum leptin concentration were analyzed using linear mixed models. Overweight/obese women had significantly higher serum leptin concentrations than their nonoverweight counterparts throughout pregnancy (P < 0.01). Although these concentrations increased significantly across gestation for both groups, the rate of increase was significantly smaller for overweight/obese women (P < 0.05). To investigate whether these differences merely reflected differences in weight‐gain patterns between the two groups, we examined an index of leptin concentration per unit body weight (leptin (ng/ml)/weight (kg)). Overweight/obese women had a significantly higher index throughout pregnancy (P < 0.01). However, although this index increased significantly across pregnancy for nonoverweight women, it actually decreased significantly for overweight/obese women (P < 0.01). Our results suggest that factors other than fat mass alone influence leptin concentrations in overweight/obese women compared to normal‐weight women during pregnancy. Such factors may contribute to differences in the intrauterine environment and its influence on pregnancy outcomes in the two groups.     

Maternal nutritional programming of fetal adipose tissue development: long-term consequences for later obesity

As obesity reaches epidemic levels in the United States there is an urgent need to understand the developmental pathways leading to this condition. Obesity increases the risk of hypertension and diabetes, symptoms of which are being seen with increased incidence in children. Adipocyte development begins in the fetus and, in contrast to all other tissues whose growth ceases in late juvenile life, it has the capacity for "unlimited" growth. In normal healthy individuals, the increase in fat mass with age is accompanied by a parallel increase in cortisol sensitivity, i.e., increased glucocorticoid receptor abundance and increased activity of the enzyme 11beta hydroxysteroid dehydrogenase type 1. Enhanced adipocyte sensitivity to cortisol is promoted in offspring born to mothers that were nutrient-restricted in utero in conjunction with increased peroxisome proliferator activated receptor alpha. This adaptation only appears to be associated with greater fat mass in the offspring when maternal nutrient restriction is confined to late gestation, coincident with the period of maximal fetal growth. In these offspring, increased fat mass is accompanied by glucose intolerance and insulin resistance, in conjunction with an adipose tissue specific reduction in glucose transporter 4 abundance. In conclusion, changes in maternal and, therefore, fetal nutrient supply at specific stages of gestation have the potential to substantially increase the risk of those offspring becoming obese in later life. The extent to which changes in dietary habits, both during pregnancy and in later life, may act to contribute to the current explosion in childhood and adult obesity remains a scientific and public health challenge to us all.     

Maternal obesity at conception programs obesity in the offspring

Risk of obesity in adult life is subject to programming during gestation. To examine whether in utero exposure to maternal obesity increases the risk of obesity in offspring, we developed an overfeeding-based model of maternal obesity in rats utilizing intragastric feeding of diets via total enteral nutrition. Feeding liquid diets to adult female rats at 220 kcal/kg(3/4) per day (15% excess calories/day) compared with 187 kcal/kg(3/4) per day for 3 wk caused substantial increase in body weight gain, adiposity, serum insulin, leptin, and insulin resistance. Lean or obese female rats were mated with ad libitum AIN-93G-fed male rats. Exposure to obesity was ensured to be limited only to the maternal in utero environment by cross-fostering pups to lean dams having ad libitum access to AIN-93G diets throughout lactation. Numbers of pups, birth weight, and size were not affected by maternal obesity. Male offspring from each group were weaned at postnatal day (PND)21 to either AIN-93G diets or high-fat diets (45% fat calories). Body weights of offspring from obese dams did not differ from offspring of lean dams when fed AIN-93G diets through PND130. However, offspring from obese dams gained remarkably greater (P < 0.005) body weight and higher % body fat when fed a high-fat diet. Body composition was assessed by NMR, X-ray computerized tomography, and weights of adipose tissues. Adipose histomorphometry, insulin sensitivity, and food intake were also assessed in the offspring. Our data suggest that maternal obesity at conception leads to fetal programming of offspring, which could result in obesity in later life.     

Size at birth, postnatal growth and risk of obesity

Epidemiological studies over the last 15 years have shown that size at birth, early postnatal catch-up growth and excess childhood weight gain are associated with an increased risk of adult cardiovascular disease and type 2 diabetes. At the same time, rising rates of obesity and overweight in children, even at pre-school ages, have shifted efforts towards the identification of very early factors that predict risk of subsequent obesity, which may allow early targeted interventions. Overall, higher birth weight is positively associated with subsequent greater body mass index in childhood and later life; however, the relationship is complex. Higher birth weight is associated with greater subsequent lean mass, rather than fat mass. In contrast, lower birth weight is associated with a subsequent higher ratio of fat mass to lean mass, and greater central fat and insulin resistance. This paradoxical effect of lower birth weight is at least partly explained by the observation that infants who have been growth restrained in utero tend to gain weight more rapidly, or 'catch up', during the early postnatal period, which leads to increased central fat deposition. There is still debate as to whether there are critical early periods for obesity: does excess weight gain during infancy, childhood or even very early neonatal life have a greater impact on long-term fat deposition and insulin resistance? Early identification of childhood obesity risk will be aided by identification of maternal and fetal genes that regulate fetal nutrition and growth, and postnatal genes that regulate appetite, energy expenditure and the partitioning of energy intake into fat or lean tissue growth.     

Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable

Background

The developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis.

Methods and Findings

We explored this hypothesis by comparing the associations of maternal and paternal pre-pregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)–determined fat mass measured at 9 to 11 y (4,091 parent–offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was −0.08 (95% CI: −0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17).

Conclusions

Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9–11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic.     

Nutritional regulation of fetal growth and implications for productive life in ruminants

The maternal nutritional and metabolic environment is critical in determining not only the reproductive success but also the long-term health and viability of the offspring. Changes in maternal diet at defined stages of gestation coincident with different stages of development can have pronounced effects on organ and tissue function in later life. This includes adipose tissue for which differential effects are observed between brown and white adipose tissues. One early, critical window of organ development in the ruminant relates to the period covering uterine attachment, or implantation, and rapid placental growth. During this period, there is pronounced cell division within developing organelles in many fetal tissues, leading to their structural development. In sheep, a 50% global reduction in caloric intake over this specific period profoundly affects placental growth and morphology, resulting in reduced placentome weight. This occurs in conjunction with a lower capacity to inactivate maternal cortisol through the enzyme 11β-hydroxysteroid dehydrogenase type 2 in response to a decrease in maternal plasma cortisol in early gestation. The birth weight of the offspring is, however, unaffected by this dietary manipulation and, although they possess more fat, this adaptation does not persist into adulthood when they become equally obese as those born to control fed mothers. Subsequently, after birth, further changes in fat development occur which impact on both glucocorticoid action and inflammatory responses. These adaptations can include changes in the relative populations of both brown and white adipocytes for which prolactin acting through its receptor appears to have a prominent role. Earlier when in utero nutrient restricted (i.e. between early-to-mid gestation) offspring are exposed to an obesogenic postnatal environment; they exhibit an exaggerated insulin response, which is accompanied by a range of amplified and thus, adverse, physiological or metabolic responses to obesity. These types of adaptations are in marked contrast to the effect of late gestational nutrient restriction, which results in reduced fat mass at birth. As young adults, however, fat mass is increased and, although basal insulin is unaffected, these offspring are insulin resistant. In conclusion, changes in nutrient supply to either the mother and/or her fetus can have profound effects on a range of metabolically important tissues. These have the potential to either exacerbate, or protect from, the adverse effects of later obesity and accompanying complications in the resulting offspring.     

Late but not early gestational maternal growth hormone treatment increases fetal adiposity in overnourished adolescent sheep

In the overnourished adolescent sheep, maternal tissue synthesis is promoted at the expense of placental growth and leads to a major decrease in lamb birth weight at term. Maternal growth hormone (GH) concentrations are attenuated in these pregnancies, and it was recently demonstrated that exogenous GH administration throughout the period of placental proliferation stimulates uteroplacental and fetal development by Day 81 of gestation. The present study aimed to determine whether these effects persist to term and to establish whether GH affects fetal growth and body composition by increasing placental size or by altering maternal metabolism. Adolescent recipient ewes were implanted with singleton embryos on Day 4 postestrus. Three groups of ewes offered a high dietary intake were injected twice daily with recombinant bovine GH from Days 35 to 65 of gestation (high intake plus early GH) or from Days 95 to 125 of gestation (high intake plus late GH) or remained untreated (high intake only). A fourth moderate-intake group acted as optimally nourished controls. Pregnancies were terminated at Day 130 of gestation (6 per group) or were allowed to progress to term (8-10 per group). GH administration elevated maternal plasma concentrations of GH, insulin, glucose, and nonesterified fatty acids during the defined treatment windows, while urea concentrations were decreased. At Day 130, GH treatment had reduced the maternal adiposity score, percentage of fat in the carcass, and internal fat depots and leptin concentrations, predominantly in the high-intake plus late GH group. Placental weight was lower in high-intake vs. control dams but independent of GH treatment. In contrast, fetal weight was elevated by late GH treatment, and these fetuses had higher relative carcass fat content, perirenal fat mass, and liver glycogen concentrations than all other groups. Expression of leptin mRNA in fetal perirenal fat and fetal plasma leptin concentrations were not significantly altered by maternal nutritional intake or GH. In pregnancies proceeding to term, the duration of gestation, fetal placental mass, and lamb birth weight were reduced in high-intake compared with control dams but were not significantly affected by GH treatment. In conclusion, exogenous GH has profound effects on maternal endocrinology, metabolism, and body composition when administered during early and late pregnancy. Treatment during late pregnancy has a modest effect on fetal growth independent of placental size and a profound effect on fetal adiposity, which may have implications beyond the fetal period.     

2型糖尿病内脏脂肪含量与胰岛β细胞功能及胰岛素抵抗的关系研究

目的:研究2型糖尿病患者内脏脂肪含量与胰岛β细胞功能及胰岛素抵抗的关系。方法:对65例初诊2型糖尿病患者采用256 CT平脐经L4、5水平进行扫描并测量皮下及内脏脂肪含量,并以BMI不同进行分组,即体重正常组、超重组、肥胖组。采用稳态模式评估法(HOMA)计算胰岛素抵抗指数、胰岛B细胞分泌功能,测量入组患者的相关人体指标、空腹血生化检查指标。结果:超体重组、肥胖组患者腰围、体重指数(body mass index, BMI)、甘油三酯(triglyceride, TG)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)、空腹血糖,(fasting blood-glucose, FBG)、空腹胰岛素(fasting insulin, FINS)INS、稳态模型胰岛素抵抗指数(Homeostatic Model Assessment for Insulin Resistance, HOMA-IR)、胰岛β细胞功能指数(Homeostasis model assessment-β,HOMA-β)指标肥胖组、超重组均明显高于正常体重组(P0.05),超体重组、肥胖组内脏脂肪含量、内脏脂肪面积、皮下脂肪含量、脂肪总含量、脂肪百分比,超重组、肥胖组均明显高于正常体重组(P0.05),且肥胖组各项指标明显高于超重组(P0.05)。多元回归分析显示腹部脂肪总含量、内脏脂肪含量、皮下脂肪含量、内脏脂肪面积、BMI与胰岛素抵抗呈正相关,而其中内脏脂肪含量及面积关系最密切。结论:内脏脂肪含量是2型糖尿病胰岛素抵抗及B细胞功能变化的独立影响因素。     

Adverse fetal and neonatal outcomes associated with a life-long high fat diet: role of altered development of the placental vasculature

Maternal obesity results in a number of obstetrical and fetal complications with both immediate and long-term consequences. The increased prevalence of obesity has resulted in increasing numbers of women of reproductive age in this high-risk group. Since many of these obese women have been subjected to hypercaloric diets from early childhood we have developed a rodent model of life-long maternal obesity to more clearly understand the mechanisms that contribute to adverse pregnancy outcomes in obese women. Female Sprague Dawley rats were fed a control diet (CON--16% of calories from fat) or high fat diet (HF--45% of calories from fat) from 3 to 19 weeks of age. Prior to pregnancy HF-fed dams exhibited significant increases in body fat, serum leptin and triglycerides. A subset of dams was sacrificed at gestational day 15 to evaluate fetal and placental development. The remaining animals were allowed to deliver normally. HF-fed dams exhibited a more than 3-fold increase in fetal death and decreased neonatal survival. These outcomes were associated with altered vascular development in the placenta, as well as increased hypoxia in the labyrinth. We propose that the altered placental vasculature may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival.     

Embryonic programming of heart disease in response to obesity during pregnancy

Obesity during pregnancy programs adult-onset heart disease in the offspring. Clinical studies indicate that exposure to an adverse environment in utero during early, as compared to late, gestation leads to a higher prevalence of adult-onset heart disease. This suggests that the early developing heart is particularly sensitive to an adverse environment. Accordingly, growing evidence from clinical studies and animal models demonstrates that obesity during pregnancy alters the function of the fetal heart, programming a higher risk of cardiovascular disease later in life. Moreover, gene expression patterns and signaling pathways that promote initiation and progression of cardiovascular disease are altered in the hearts in offspring born to obese mothers. However, the mechanisms mediating the long-term effects of an adverse environment in utero on the developing heart leading to adult-onset disease are not clear. Here, we review clinical and experimental evidence documenting the effects of maternal obesity during pregnancy on the fetal and post-natal heart and emphasize on the potential mechanisms of disease programming.     

Maternal serum lipids during pregnancy and infant birth weight: the influence of prepregnancy BMI

Maternal obesity may be associated with metabolic factors that affect the intrauterine environment, fetal growth, and the offspring's long-term risk for chronic disease. Among these factors, maternal serum lipids play a particularly important role. Our objective was to estimate the influence of variation in maternal serum lipid levels on variation in infant birth weight (BW) in overweight/obese and normal weight women. In a prospective cohort of 143 gravidas, we measured maternal serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) at 6-10, 10-14, 16-20, 22-26, and 32-36 weeks gestation. Effects of maternal serum lipid levels on infant BW adjusted for gestational age at delivery (aBW) were analyzed using linear regression models. In analyses stratified by maternal prepregnancy BMI categorized as normal (≤25.0 kg/m(2)) and overweight/obese (>25.0 kg/m(2)), we found a significant (P < 0.05) inverse association between aBW and HDL-C at all time points starting at 10 weeks gestation in overweight/obese women. No significant effect was found in normal weight women. In contrast, increased maternal serum TG was significantly associated with increased aBW only for normal weight women at 10-14 and 22-26 weeks gestation. Variation in aBW is not associated with variation in maternal serum TC or LDL-C for either stratum at any time point. We postulate that such differences may be involved in the "physiological programming" that influences later risk of chronic disease in the infants of overweight/obese mothers.     

Maternal-fetal hepatic and placental metabolome profiles are associated with reduced fetal growth in a rat model of maternal obesity

Introduction

Maternal obesity is associated with a range of pregnancy complications, including fetal growth restriction (FGR), whereby a fetus fails to reach its genetically determined growth. Placental insufficiency and reduced nutrient transport play a role in the onset of FGR.

Objectives

Metabolomic profiling was used to reveal altered maternal and fetal metabolic pathways in a model of diet induced obesity during pregnancy, leading to reduced fetal growth.

Methods

We examined the metabolome of maternal and fetal livers, and placenta following a high fat and salt intake. Sprague–Dawley rats were assigned to (a) control diet (CD; 1 % salt, 10 % kcal from fat), (b) high salt diet (SD; 4 % salt, 10 % kcal from fat), (c) high fat diet (HF; 1 % salt, 45 % kcal from fat) or (d) high-fat high-salt diet (HFSD; 4 % salt, 45 % kcal from fat) 21 days prior to pregnancy and during gestation. Metabolites from maternal and fetal livers, and placenta were identified using gas and liquid chromatography combined with mass spectrometry.

Results

Maternal HF intake resulted in reduced fetal weight. Altered metabolite profiles were observed in the HF maternal and fetal liver, and placenta. Polyunsaturated fatty acid metabolism was significantly altered in maternal and fetal liver by maternal fat intake.

Conclusion

Excess of linoleic and α-linoleic acid (essential fatty acids) may be detrimental during placentation and associated with a reduction in fetal weight. Additionally, maternal, placental and fetal response to increased fat consumption seems likely to involve palmitoleic acid utilization as an adaptive response during maternal obesity.