Rohan M. Lewis

Early programming of weight gain in mice prevents the induction of obesity by a highly palatable diet.

Poor early growth is associated with Type II diabetes, hypertension and other features of the metabolic syndrome in adulthood. It has been suggested that this results from the development of a thrifty phenotype by a malnourished fetus. Such a phenotype would predispose the offspring to the development of obesity if born into conditions of over-nutrition. The present study aimed to determine if early nutrition affected subsequent development of obesity. Mice were established as follows: (a) controls (offspring of control dams), (b) recuperated (offspring of dams fed a low-protein diet during pregnancy, but nursed by control dams) and (c) postnatal low-protein (offspring of control dams nursed by low-protein-fed dams). Mice were weaned on to standard laboratory chow or a cafeteria diet. Recuperated offspring, although smaller at birth ( P <0.01), caught up and exceeded the weight of control offspring by 7 days of age ( P <0.001). Postnatal low-protein offspring were smaller than controls by 7 days of age ( P <0.001). Recuperated animals gained more weight than controls when given free access to a highly palatable diet ( P <0.01). Postnatal low-protein animals showed no additional weight gain when given a highly palatable diet compared with chow-fed litter-mates. These results suggest that the early environment has long-term consequences for weight gain. These programmed responses are powerful enough to block excess weight gain from a highly palatable diet and, thus, have major implications for the drug-free regulation of food intake and obesity.

Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring.

In rats, maternal anaemia during pregnancy causes hypertension in the adult offspring, although the mechanism is unknown. The present study investigated the renal morphology of adult rats born to mothers who were Fe-deficient during pregnancy. Rats were fed either a control (153 mg Fe/kg diet, n 7) or low-Fe (3 mg/kg diet, n 6) diet from 1 week before mating and throughout gestation. At delivery, the Fe-restricted (IR) mothers were anaemic; the IR pups were also anaemic and growth-retarded at 2 d of age. At 3 and 16 months, systolic blood pressure in the IR offspring (163 (sem 4) and 151 (sem 4) mmHg respectively, n 13) was greater than in control animals (145 (sem 3) and 119 (sem 4) mmHg respectively, n 15, P<0.05). At post mortem at 18 months, there was no difference in kidney weight between treatment groups, although relative kidney weight as a fraction of body weight in the IR offspring was greater than in control animals (P<0.05). Glomerular number was lower in the IR offspring (11.4 (sem 1.1) per 4 mm(2), n 13) compared with control rats (14.8 (sem 0.7), n 15, P<0.05). Maternal treatment had no effect on glomerular size, but overall, female rats had smaller and more numerous glomeruli per unit area than male rats. When all animals were considered, inverse relationships were observed between glomerular number and glomerular size (r-0.73, n 28, P<0.05), and glomerular number and systolic blood pressure at both 3 months (r-0.42, n 28, P<0.05) and 16 months of age (r-0.64, n 28, P<0.05). Therefore, in rats, maternal Fe restriction causes hypertension in the adult offspring that may be due, in part, to a deficit in nephron number.

The Mechanisms and Regulation of Placental Amino Acid Transport to the Human Foetus

The mechanisms by which amino acids are transferred across the human placenta are fundamental to our understanding of foetal nutrition. Amino acid transfer across the human placenta is dependent on transport across both the microvillous and basal plasma membranes of the placental syncytiotrophoblast, and on metabolism within the syncytiotrophoblast. Although the principles underlying uptake of amino acids across the microvillous plasma membrane are well understood, the extent to which amino acids are metabolised within human placenta and the mechanisms by which amino acids are transported out of the placenta across the basal plasma membrane are not well understood. Understanding the mechanisms and regulation of amino acid transport is necessary to understand the causes of intrauterine growth restriction in human pregnancy.

Long-term programming of blood pressure by maternal dietary iron restriction in the rat

We have reported that blood pressure was elevated in 3-month-old rats whose mothers were Fe-restricted during pregnancy. These animals also had improved glucose tolerance and decreased serum triacylglycerol. The aim of the present study was to determine whether these effects of maternal nutritional restriction, present in these animals at 3 months of age, can be observed in the same animals in later life. Pulmonary and serum angiotensin converting enzyme (ACE) concentrations were also measured to investigate whether the renin-angiotensin system was involved in the elevation of blood pressure observed in the offspring of Fe-restricted dams. Systolic blood pressure was higher in the offspring of Fe-restricted dams at 16 months of age. Heart and kidney weight were increased as a proportion of body weight in the offspring of Fe-restricted dams. The pulmonary ACE concentration was not significantly different between the groups. The serum ACE concentration was significantly elevated in the offspring of Fe-restricted dams at 3 but not 14 months of age. There was a strong correlation between serum ACE levels at 3 and 14 months of age. Glucose tolerance and serum insulin were not different between the maternal diet groups. Serum triacylglycerol tended to be lower in the offspring of Fe-restricted dams. There were no differences in serum non-esterified fatty acids or serum cholesterol between the maternal diet groups. This study provides further evidence that maternal nutrition has effects on the offspring that persist throughout life. At 16 months of age, the elevation of blood pressure in Fe-restricted offspring does not appear to be mediated via changes in ACE levels. Both cardiac hypertrophy and decreased serum triacylglycerol have also been observed in Fe-restricted fetuses, suggesting that these changes may be initiated in utero.

Review: Placenta, evolution and lifelong health

The intrauterine environment has an important influence on lifelong health, and babies who grew poorly in the womb are more likely to develop chronic diseases in later life. Placental function is a major determinant of fetal growth and is therefore also a key influence on lifelong health. The capacity of the placenta to transport nutrients to the fetus and regulate fetal growth is determined by both maternal and fetal signals. The way in which the placenta responds to these signals will have been subject to evolutionary selective pressures. The responses selected are those which increase Darwinian fitness, i.e. reproductive success. This review asks whether in addition to responding to short-term signals, such as a rise in maternal nutrient levels, the placenta also responds to longer-term signals representing the mothers phenotype as a measure of environmental influences across her life course. Understanding how the placenta responds to maternal signals is therefore not only important for promoting optimal fetal growth but can also give insights into how human evolution affected developmental history with long-term effects on health and disease.

Effects of maternal iron restriction in the rat on hypoxia-induced gene expression and fetal metabolite levels

The mechanism by which maternal Fe deficiency in the rat causes fetal growth retardation has not been clearly established. This study compared the effects on the fetuses from dams fed a control diet with two groups of dams fed Fe-restricted diets. One Fe-restricted group was fed the Fe-restricted diet for 1 week prior to mating and throughout gestation and the second Fe-restricted group was fed the Fe-restricted diet for 2 weeks prior to mating and throughout gestation. On day 21 of gestation Fe-restricted dams, and their fetuses, were anaemic. Fetal weight was reduced in both Fe-restricted groups compared with controls. Expression of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) are induced by hypoxia. The levels of HIF-1alpha mRNA were highest in placenta, then in kidney, heart and liver but were not different between the groups. Levels of plasma VEGF were not different between the groups. Maternal plasma triacylglycerol was decreased in the 1-week Fe-restricted dams compared with controls. Maternal plasma cholesterol and free fatty acid levels were not different between the groups. In fetal plasma, levels of triacylglycerol and cholesterol were decreased in both Fe-restricted groups. In maternal plasma, levels of a number of amino acids were elevated in both Fe-restricted groups. In contrast, levels of a number of amino acids in fetal plasma were lower in both Fe-restricted groups. Fetal plasma lactate was increased in Fe-restricted fetuses but fetal plasma glucose and beta-hydroxybutyrate were not affected. These changes in fetal metabolism may contribute to fetal growth retardation in this model. This study does not support the hypothesis that the Fe-restricted fetus is hypoxic.

Facilitated transporters mediate net efflux of amino acids to the fetus across the basal membrane of the placental syncytiotrophoblast

Non‐technical summary Fetal growth depends on transfer of amino acids from the mother to the fetus via the placenta: the interface between the maternal and fetal circulations. We know how amino acids enter the placenta from the maternal blood, but it was not known how the amino acids exit the placenta to reach the fetus. Our work has now provided the first experimental evidence for a novel transport system which provides net amino acid transport to the fetus and influences fetal growth.

Modification of fetal plasma amino acid composition by placental amino acid exchangers in vitro

Fetal growth is dependent on both the quantity and relative composition of amino acids delivered to the fetal circulation, and impaired placental amino acid supply is associated with restricted fetal growth. Amino acid exchangers can alter the composition, but not the quantity, of amino acids in the intra‐ and extracellular amino acid pools. In the placenta, exchangers may be important determinants of the amino acid composition in the fetal circulation. This study investigates the substrate specificity of exchange between the placenta and the feto‐placental circulation. Maternal–fetal transfer of radiolabelled amino acids and creatinine were measured in the isolated perfused human placental cotyledon. Transfer of l‐[14C]serine or l‐[14C]leucine, and [3H]glycine, were measured in the absence of amino acids in the fetal circulation (transfer by non‐exchange mechanisms) and following 10–20 μmol boluses of unlabelled amino acids into the fetal circulation to provide substrates for exchange (transfer by exchange and non‐exchange mechanisms). The ability of fetal arterial boluses of l‐alanine and l‐leucine to stimulate release of amino acids from the placenta was also determined using HPLC in order to demonstrate the overall pattern of amino acid release. Experiments with radiolabelled amino acids demonstrated increased maternal–fetal transfer of l‐serine and l‐leucine, but not glycine, following boluses of specific amino acids into the fetal circulation. l‐[14C]Leucine, but not l‐[14C]serine or [3H]glycine, was transferred from the maternal to the fetal circulation by non‐exchange mechanisms also (P < 0.01). HPLC analysis demonstrated that fetal amino acid boluses stimulated increased transport of a range of different amino acids by 4–7 μmol l−1 (P < 0.05). Amino acid exchange provides a mechanism to supply the fetus with amino acids that it requires for fetal growth. This study demonstrates that these transporters have the capacity to exchange micromolar amounts of specific amino acids, and suggests that they play an important role in regulating fetal plasma amino acid composition.

Perinatal Growth Disturbance in the Spontaneously Hypertensive Rat

Disproportionate fetal and placental growth are associated with the development of hypertension in the rat and human. Here we report differences in fetal, neonatal, and placental growth, and in metabolism and endocrinology, between the spontaneously hypertensive rat (SHR), a genetic model for human essential hypertension, and the control Wistar-Kyoto (WKY) strain. Gestation in SHR (23 d) was longer than in WKY by 20 h. Body weights were lower in the SHR from fetal d 16 to 20 and on postnatal d 15. However, on fetal d 22 and postnatal d 1, there was no significant difference in body weight between SHR and WKY. SHR placentas were larger than those of WKY at d 20, and by term there was a difference of 30% (p < 0.01). Other indices of disproportionate growth were hypertrophy of the fetal heart and kidney and decreased ponderal index in the SHR neonate. Blood glucose in SHR fetuses was lower than in WKY fetuses (p < 0.05), whereas blood lactate was higher (p < 0.05) and fetal hematocrit was reduced (p< 0.001). These findings suggest undernutrition and placental insufficiency may occur in SHR fetuses. Plasma IGF-II was increased on the last day of gestation in both strains, whereas IGF-I was unaltered. Fetal liver IGFBP-2 mRNA and plasma IGFBP-2 levels were reduced in SHR on fetal d 20 and 22(p < 0.01). Differences in growth and endocrine and metabolic parameters suggest abnormal perinatal physiology in the SHR, which may influence the later development of hypertension.

Maternal muscle mass may influence system A activity in human placenta.

During pregnancy, nutrient partitioning between the mother and fetus must balance promoting fetal survival and maintaining nutritional status of the mother for her health and future fertility. The nutritional status of the pregnant woman, reflected in her body composition, may affect placental function with consequences for fetal development. We investigated the relationship between maternal body composition and placental system A amino acid transporter activity in 103 term placentas from Southampton Womens Survey pregnancies. Placental system A activity was measured as Na(+)-dependent uptake of 10 mumol/L (14)C-methylaminoisobutyric acid (a system A specific amino acid analogue) in placental villous fragments. Maternal body composition was measured at enrollment pre-pregnancy; in 45 infants neonatal body composition was measured using dual-energy x-ray absorptiometry. Term placental system A activity was lower in women with smaller pre-pregnancy upper arm muscle area (r = 0.27, P = 0.007), but was not related to maternal fat mass. System A activity was lower in mothers who reported undertaking strenuous exercise (24.6 vs 29.7 pmol/mg/15 min in sedentary women, P = 0.03), but was not associated with other maternal lifestyle factors. Lower placental system A activity in women who reported strenuous exercise and had a lower arm muscle area may reflect an adaptation in placental function which protects maternal resources in those with lower nutrient reserves. This alteration may affect fetal development, altering fetal body composition, with long-term consequences.