Sex-dependent vulnerability of fetal nonhuman primate cardiac mitochondria to moderate maternal nutrient reduction.

Poor maternal nutrition in pregnancy affects fetal development, predisposing offspring to cardiometabolic diseases. The role of mitochondria during fetal development on later-life cardiac dysfunction caused by maternal nutrient reduction (MNR) remains unexplored. We hypothesized that MNR during gestation causes fetal cardiac bioenergetic deficits, compromising cardiac mitochondrial metabolism and reserve capacity. To enable human translation, we developed a primate baboon model (Papio spp.) of moderate MNR in which mothers receive 70% of control nutrition during pregnancy, resulting in intrauterine growth restriction (IUGR) offspring and later exhibiting myocardial remodeling and heart failure at human equivalent ∼25 years. Term control and MNR baboon offspring were necropsied following cesarean-section, and left ventricle (LV) samples were collected. MNR adversely impacted fetal cardiac LV mitochondria in a sex-dependent fashion. Increased maternal plasma aspartate aminotransferase, creatine phosphokinase (CPK), and elevated cortisol levels in MNR concomitant with decreased blood insulin in male fetal MNR were measured. MNR resulted in a two-fold increase in fetal LV mitochondrial DNA (mtDNA). MNR resulted in increased transcripts for several respiratory chain (NDUFB8, UQCRC1, and cytochrome c) and adenosine triphosphate (ATP) synthase proteins. However, MNR fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, possibly contributing to the 73% decreased ATP content and increased lipid peroxidation. MNR fetal LV showed mitochondria with sparse and disarranged cristae dysmorphology. Conclusion: MNR disruption of fetal cardiac mitochondrial fitness likely contributes to the documented developmental programming of adult cardiac dysfunction, indicating a programmed mitochondrial inability to deliver sufficient energy to cardiac tissues as a chronic mechanism for later-life heart failure.

Impairment of microvascular angiogenesis is associated with delay in prostatic development in rat offspring of maternal protein malnutrition.

Experimental data demonstrated the negative impact of maternal protein malnutrition (MPM) on rat prostate development, but the mechanism behind the impairment of prostate growth has not been well understood. Male Sprague Dawley rats, borned to dams fed a normal protein diet (CTR group, 17% protein diet), were compared with those borned from dams fed a low protein diet (6% protein diet) during gestation (GLP group) or gestation and lactation (GLLP). The ventral prostate lobes (VP) were removed at post-natal day (PND) 10 and 21, and analyzed via different methods. The main findings were low birth weight, a reduction in ano-genital distance (AGD, a testosterone-dependent parameter), and an impairment of prostate development. A delay in prostate morphogenesis was associated with a reduced testosterone levels and angiogenic process through downregulation of aquaporin-1 (AQP-1), insulin/IGF-1 axis and VEGF signaling pathway. Depletion of the microvascular network, which occurs in parallel to the impairment of proliferation and differentiation of the epithelial cells, affects the bidirectional flux between blood vessels impacting prostatic development. In conclusion, our data support the hypothesis that a reduction in microvascular angiogenesis, especially in the subepithelial compartment, is associated to the impairment of prostate morphogenesis in the offspring of MPM dams.

Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming.

BACKGROUND: Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring. RESULTS: We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that "leptin reversal" is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring. CONCLUSIONS: We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This "calibration model" for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.

Canalization and developmental instability of the fetal skull in a mouse model of maternal nutritional stress.

Nutritional imbalance is one of the main sources of stress in both extant and extinct human populations. Restricted availability of nutrients is thought to disrupt the buffering mechanisms that contribute to developmental stability and canalization, resulting in increased levels of fluctuating asymmetry (FA) and phenotypic variance among individuals. However, the literature is contradictory in this regard. This study assesses the effect of prenatal nutritional stress on FA and among-individual variance in cranial shape and size using a mouse model of maternal protein restriction. Two sets of landmark coordinates were digitized in three dimensions from skulls of control and protein restricted specimens at E17.5 and E18.5. We found that, by the end of gestation, maternal protein restriction resulted in a significant reduction of skull size. Fluctuating asymmetry in size and shape exceeded the amount of measurement error in all groups, but no significant differences in the magnitude of FA were found between treatments. Conversely, the pattern of shape asymmetry was affected by the environmental perturbation since the angles between the first eigenvectors extracted from the covariance matrix of shape asymmetric component of protein restricted and control groups were not significantly different from the expected for random vectors. In addition, among-individual variance in cranial shape was significantly higher in the protein restricted than the control group at E18.5. Overall, the results obtained from a controlled experiment do not support the view of fluctuating asymmetry of cranial structures as a reliable index for inferring nutritional stress in human populations.

Associations between placental pathology and poor intrauterine growth among a cohort of mother-infant singleton pairs in Leyte, the Philippines.

OBJECTIVE: Poor intrauterine growth has negative impacts for child growth and development and disproportionately affects children living in low-resource settings. In the present study, we investigated relationships between placental pathologies and indicators of poor intrauterine growth. METHODS: We enrolled a longitudinal cohort of 279 mother-infant pairs from Leyte, the Philippines. Placental measures included characteristics, pathological findings, and immunohistochemistry. At birth, intrauterine growth was assessed using anthropometric measures, weight-for-gestational age, and the clinical assessment of nutritional status score (CANSCORE) for determining fetal malnutrition. Multivariate linear regression and log-binomial regression models were applied, controlling for potential confounding factors. RESULTS: Maternal vascular malperfusion (MVM) was related to reduced birthweight (P < 0.0001), birth length (P = 0.002), head circumference (P = 0.001), and weight-to-length ratio (P = 0.016). MVM increased the risk for preterm delivery (P = 0.0005) and small for gestational age (SGA) (P = 0.016). Acute chorioamnionitis (P = 0.013) and MVM (P = 0.021) both led to an increased risk for fetal malnutrition defined by CANSORE<25. Villous tissue activated caspase-3 was associated with lower birth length (P = 0.0006), higher weight-to-length ratio (P = 0.004), reduced risks for SGA (P = 0.011) and low weight-to-length ratio for gestational age (P = 0.004). CONCLUSION: The present study applied comprehensive measures for intrauterine growth and demonstrates that low placental weight and placental pathology, chiefly MVM, contribute to poor intrauterine growth. A better understanding of the mechanistic role of specific placental pathologies on adverse newborn outcomes will provide opportunities for reducing incidence of poor intrauterine growth and associated long-term morbidities.

Maternal and Placental Risk Factors for Small Gestational Age and Fetal Malnutrition.

AIMS: This case-control study was conducted to identify maternal and placental risk factors of small-for-gestational-age (SGA) and fetal malnutrition. METHODS: Cases comprised 104 consecutively delivered SGA neonates (determined as per INTERGROWTH- 21st standard). An equal number of next-born gestation and gender-matched appropriatefor- gestational age (AGA) neonates served as controls. Maternal risk factors were enquired, and placentae were evaluated by clinical and histopathological examination. Nutrition of the neonates was assessed by the clinical assessment of nutrition (CAN) score. Univariate and multivariate logistic regression analysis was done to identify the maternal and placental risk factors. RESULTS: The prevalence of SGA in the present study was 23.9%. Maternal fever [adjusted Odds Ratio (aOR), 95% confidence interval (CI), 16.3 (3.5-124.1); p = 0.001], presence of placental syncytial knots [aOR (95% CI), 2.9 (1.1-9.1); p = 0.04] and placental calcifications [aOR (95% CI), 3(1.1- 8.7); p = 0.03], were identified as independent predictors of SGA using multivariate logistic regression analysis. Malnutrition (SCORE <25) affected 64% of SGA and 16.3% of AGA neonates. The only risk factor significantly associated with malnourished SGA was prematurity, whereas malnourished AGA was significantly associated with prematurity and fetal distress. In-hospital morbidities significantly higher in SGA were perinatal asphyxia, respiratory distress, need for respiratory support, polycythemia, hypoglycemia, and feeding intolerance. Mortality before discharge was 4.8% and 3.8% in SGA and AGA population, respectively (p > 0.05). Neonatal outcomes were comparable among well-nourished, malnourished SGA and AGA groups. CONCLUSION: Maternal fever, placental syncytial knots, and calcifications were independent risk factors of SGA, whereas prematurity and fetal distress were responsible for malnutrition.

Frequency and risk factors of fetal malnutrition among liveborn singleton term neonates using a computerised perinatal database, 2000-2006.

AIM: The aim of this study was to determine the frequency, risk factors and anthropometric measurements of fetally malnourished, liveborn singleton term neonates. METHODS: The computed delivery room data of 11.741 liveborn singleton term neonates was used to compare malnourished and nourished newborns. RESULTS: Of the total subjects, 577 (4.9%) were malnourished. There were no differences between the groups with regard to gender distribution, Apgar scores, maternal parity, smoking during pregnancy and type of delivery. Maternal age and neonatal gestational age (GA) were significantly lower in malnourished newborns (P < 0.001). Birthweight (BW), birth length (BL) and head circumference (HC) were significantly lower in the malnourished group compared with well-nourished group (P < 0.001). Mean BW (g) was 2724.7 ± 17.0 in the malnourished group versus 3234.3 ± 3.8 in the well-nourished group; BL (cm) was 47.8 ± 0.1 in malnourished versus 49.5 ± 0.0 in well-nourished neonates; HC (cm) was 33.25 ± 0.1 in the malnourished versus 34.3 ± 0.0 in the well-nourished group. Between the groups, there were significant differences in the ratio of small, appropriate and large for GA (P < 0.001). Of the malnourished newborns, 35.5% were small for GA, 63.3% were appropriate for GA and 1.2% were large for GA. CONCLUSION: Fetal malnutrition (FM) still exists despite the advances in current obstetric care. Neonates of adolescent mothers and of low GA are particularly at risk for FM. The BW, BL and HC of fetally malnourished neonates are lower than that of well-nourished neonates. Like term singleton appropriate and small for GA neonates, term singleton large for GA neonates could also have been fetally malnourished.

Perinatal copper deficiency alters rat cerebellar purkinje cell size and distribution.

Copper is required for activity of several key enzymes and for optimal mammalian development, especially within the central nervous system. Copper-deficient (CuD) animals are visibly ataxic, and previous studies in rats have demonstrated impaired motor function through behavioral experiments consistent with altered cerebellar development. Perinatal copper deficiency was produced in Holtzman rat dams by restricting dietary copper during the last two thirds of gestation and lactation. Male offspring were evaluated at postnatal day 25. Compared to cerebella from copper-adequate pups, the CuD pups had larger Purkinje cell (PC) size and irregularities in the Purkinje cell monolayer. These results suggest that the ataxic behavioral phenotype of CuD rats may result from disrupted inhibitory pathways in the cerebellum. A similar PC phenotype is seen in Menkes disease and in mottled mouse mutants with genetic copper deficiency, suggesting that copper deficiency and not just specific loss of ATP7A function is responsible.

Micro-anatomic alterations of the placenta in a non-human primate model of gestational protein-restriction.

OBJECTIVES: Maternal protein malnutrition is associated with impaired fetal growth, and lifetime consequences for the offspring. Our group has previously developed a model of protein-restriction in the non-human primate, which was associated with fetal growth restriction, stillbirth, decreased placental perfusion, and evidence of fetal hypoxia, suggesting perturbed vascular development. Our objective was to histologically characterize the micro-anatomic alterations associated with adverse pregnancy outcomes taking an approach that permits investigation of the 3D vascular structure and surrounding histology without the requirement for 3D vascular casting or relying on 2D stereology which both have methodological limitations. METHODS: Rhesus macaques were assigned in the pre-gestational period to a control diet that contained 26% protein, or study diet containing 13% protein (50% PR diet). Placental tissue was collected at delivery and processed using a clarification, immunohistochemistry, and confocal microscopy protocol published previously by our group. Three dimensional reconstructions and quantitative assessment of the vascular micro-anatomy was performed using analysis software (Imaris®) and statistical analysis accounted for maternal and fetal confounders. RESULTS: In unadjusted analysis, when comparing those pregnancies on a 50% PR diet (n = 4) with those on a control diet (n = 4), protein-restriction diet was associated with decreased maternal pre-pregnancy weight (difference of -1.975kg, 95% CI -3.267 to -0.6826). When controlling for maternal pre-pregnancy weight, fetal sex, and latency from tissue collection to imaging, a gestational protein-restriction diet was associated with decreases in total vascular length, total vascular surface area, total vascular volume, and vascular density. CONCLUSION: In this pilot study, a gestational protein-restriction diet altered the placental micro-vasculature with decreased vascular caliber and density, which may be related to the observed adverse pregnancy outcomes and perturbed placental perfusion previously demonstrated in this model.

Differential impacts of late gestational over-and undernutrition on adipose tissue traits and associated visceral obesity risk upon exposure to a postnatal high-fat diet in adolescent sheep.

We hypothesized that late gestation malnutrition differentially affects expandability of adipose tissues to predispose for early postnatal visceral adiposity. Twin-lambs born to dams fed HIGH (150%/110% of required energy/protein, respectively), NORM (100% of requirements) or LOW (50% of NORM) diets during the last trimester were used. Postnatally, lambs were raised on moderate (CONV) or high-carbohydrate-high-fat (HCHF) diets. Adipose tissues were sampled at autopsy at 6 months of age (~puberty) to characterize cellularity, adipocyte cross-sectional area and gene expression patterns. HIGH and LOW compared to NORM lambs had reduced intrinsic (under CONV diet) cellularity in subcutaneous and mesenteric (particularly LOW), and reduced obesity-induced (under HCHF diet) hyperplasia in subcutaneous, mesenteric and perirenal (particularly HIGH) adipose tissues. This corresponded with more pronounced HCHF diet-induced hypertrophy in mesenteric (particularly LOW), perirenal (particularly HIGH) and subcutaneous (particularly HIGH) adipose tissues, and tissue-specific reductions in mRNA expressions for lipid metabolism, angiogenesis and adipose development. Gene expression for inflammation and lipid metabolism markers were increased and decreased, respectively, in HCHF lambs (HCHF lambs became obese) in all tissues. Both prenatal over- and undernutrition predisposed for abdominal adiposity and extreme perirenal hypertrophy due to reduced intrinsic (observed under CONV diet) cellularity and impaired ability of subcutaneous, mesenteric and perirenal adipose tissues to expand by hyperplasia rather than hypertrophy on an obesogenic (HCHF) diet.

Behavioral Feeding Circuit: Dietary Fat-Induced Effects of Inflammatory Mediators in the Hypothalamus.

Excessive dietary fat intake has extensive impacts on several physiological systems and can lead to metabolic and nonmetabolic disease. In animal models of ingestion, exposure to a high fat diet during pregnancy predisposes offspring to increase intake of dietary fat and causes increase in weight gain that can lead to obesity, and without intervention, these physiological and behavioral consequences can persist for several generations. The hypothalamus is a region of the brain that responds to physiological hunger and fullness and contains orexigenic neuropeptide systems that have long been associated with dietary fat intake. The past fifteen years of research show that prenatal exposure to a high fat diet increases neurogenesis of these neuropeptide systems in offspring brain and are correlated to behavioral changes that induce a pro-consummatory and obesogenic phenotype. Current research has uncovered several potential molecular mechanisms by which excessive dietary fat alters the hypothalamus and involve dietary fatty acids, the immune system, gut microbiota, and transcriptional and epigenetic changes. This review will examine the current knowledge of dietary fat-associated changes in the hypothalamus and the potential pathways involved in modifying the development of orexigenic peptide neurons that lead to changes in ingestive behavior, with a special emphasis on inflammation by chemokines.

The late gestation fetal cardiovascular response to hypoglycaemia is modified by prior peri-implantation undernutrition in sheep.

Undernourished late gestation fetuses display asymmetric growth restriction, suggestive of a redistribution of nutritional resources. The modification of fetal organ blood supply in response to acute hypoxia is well characterized, but it is not known whether similar responses occur in response to acute reductions in nutrition, or if such late gestation responses can be influenced by early gestation nutrition. In pregnant sheep, total nutrient requirements were restricted during the peri-implantation period (PI40, 40%; PI50, 50% of total, days 1-31) or in late gestation (L, 50% total, days 104-postmortem). Control animals were fed 100% nutrient requirements. Fetal organ blood flows were measured at baseline, and during acute fetal hypoglycaemia induced by maternal insulin infusion at 125 dGA. Baseline heart rate was increased in PI40 fetuses. During hypoglycaemia, an initial rise in fetal heart rate was followed by a slower fall. Fetal femoral artery blood flow decreased, and adrenal blood flow and femoral vascular resistance increased in all fetuses during hypoglycaemia. These changes were accompanied by increased fetal plasma adrenaline and cortisol, and reduced plasma insulin levels. The maximum femoral artery blood flow response to hypoglycaemia occurred earlier in PI50 and PI40 compared with control fetuses. The late gestation fetal cardiovascular response to acute hypoglycaemia was consistent with a redistribution of combined ventricular output away from the periphery and towards central organs. One element of the peripheral vascular response was modified by peri-implantation nutrient restriction, indicating that nutritional challenges early in gestation can have an enduring impact on cardiovascular control.

Ultrasonographic measurement of thymus size in IUGR fetuses: a marker of the fetal immunoendocrine response to malnutrition.

OBJECTIVE: To test the hypothesis that intrauterine growth restriction (IUGR) is associated with decreased thymus size in the human fetus. METHODS: The thymus perimeter was measured in 60 consecutive IUGR fetuses at prenatal ultrasound examination. IUGR was defined as an abdominal circumference (AC) <5(th) centile. Sixty controls were identified by selection of the next consecutive appropriately grown fetus of similar gestational age (+/-1 week). To exclude fetal size effects, ratios between thymus perimeter and fetal biometry measurements including biparietal diameter (BPD), AC and femur length (FL), as well as estimated fetal weight (EFW) were compared between IUGR fetuses and controls. RESULTS: The proportion of fetuses with thymus perimeter <5(th) centile for gestation was significantly higher in IUGR fetuses than in controls (58/60 vs. 7/60, P < 0.0001). The mean thymus perimeter/BPD ratio (0.87 +/- 0.20 vs. 1.13 +/- 0.13, P < 0.0001), thymus perimeter/AC ratio (0.28 +/- 0.06 vs. 0.35 +/- 0.03, P < 0.0001), thymus perimeter/FL ratio (1.18 +/- 0.26 vs. 1.51 +/- 0.19, P < 0.001) and thymus perimeter/EFW ratio (0.05 +/- 0.01 vs. 0.06 +/- 0.01, P = 0.02) were significantly lower in IUGR fetuses than in controls. There was a significant positive correlation between the observed-to-expected mean for gestation thymus perimeter ratio and the enrollment-to-delivery interval (r = 0.44, P < 0.001). CONCLUSION: IUGR is associated with a disproportionately small thymus. This supports the hypothesis that thymic involution may be part of the fetal neuroendocrine response to intrauterine starvation.

Placental findings in malnourished term neonates.

BACKGROUND: The aim of the present study was to investigate placental pathologies in malnourished term neonates. METHODS: A group of term newborns was evaluated at birth for fetal malnutrition (FM) using the Clinical Assessment of Nutritional Status (CANS) score. The study group consisted of 37 malnourished neonates and 13 well-nourished newborns, including their placentas. Infants with FM were subdivided into two groups: appropriate for gestational age (AGA) and small for gestational age (SGA). RESULTS: The proportion of subjects having antepartum complications was 18.9% in the FM group, whereas none was found in the control group. Similarly, a significant portion, 83.8% of the study group, had gross placental abnormalities, while the control group had none. The placental microscopic findings in the study group included perivillous fibrin deposition, calcification, necrosis, retroplacental hematoma, and infarction. In contrast, the control group had only perivillous fibrin deposition and calcification. Placental histopathological findings between FM term AGA and SGA neonates were also compared, and no statistically significant differences were found (P < 0.05). CONCLUSIONS: Placental findings in malnourished term AGA neonates are not different from findings documented in malnourished SGA cases, but they are different from those in well-nourished term AGA newborns.

Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups.

A growing body of evidence suggests that maternal undernutrition sensitizes the offspring to the development of energy balance metabolic disorders such as type 2 diabetes, dyslipidemia, and obesity. The present study aimed at examining the impact of maternal undernutrition on leptin plasma levels in newborn male rats and on the arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons that are major leptin targets. Using a model of perinatal maternal 50% food-restricted diet (FR50) in the rat, we evaluated leptin plasma levels and hypothalamic POMC and NPY gene expression from postnatal day (PND) 4 to PND30 in both control and FR50 offspring. In control rats, a postnatal peak of plasma leptin was observed between PND4 and PND14 that reached a maximal value at PND10 (5.17 +/- 0.53 ng/ml), whereas it was dramatically reduced in FR50 pups with the higher concentration at PND7 (0.93 +/- 0.23 ng/ml). In FR50 animals, using semiquantitative RT-PCR and in situ hybridization, we showed that the hypothalamic POMC mRNA level was decreased from PND14 until PND30, whereas NPY gene expression was not significantly modified. In PND21 FR50 animals, we observed strikingly reduced immunoreactive beta-endorphin nerve fibers projecting to the hypothalamic paraventricular nucleus without affecting NPY projections. Our data showed that maternal undernutrition drastically reduces the postnatal surge of plasma leptin, disturbing particularly the hypothalamic wiring as well as the gene expression of the anorexigenic POMC neurons in male rat pups. These alterations might contribute to the adult metabolic disorders resulting from perinatal growth retardation.

Impact of abnormal nutrition during pregnancy on the offspring hormone resistance.

OBJECTIVE: To investigate the impact of abnormal nutrition during pregnancy on the insulin and leptin resistance of adult offsprings. METHODS: The model of abnormal nutrition during pregnancy was established, and these rats were fed whole-course low-protein or high-nutrition. After natural childbirth, the birth weight of each newborn rat was measured. According to the determining birth weights, the newborn rats were assigned into the small for gestational age (SGA) and large for gestational age (LGA) groups as well as the healthy control group, respectively. There was a total of 36 randomly selected rats in each group. The levels of insulin and leptin and the insulin sensitivity index (ISI) were determined by enzymelinked immunosorbent assay 4 and 12 weeks post birth, respectively. RESULTS: In the low-protein group, the birth weight was significantly lower than in the control group (p<0.01) and 68.97% of the newborn rats were SGA; in the high-energy group, the birth weight of the newborn rats was significantly larger than in the control group (p<0.01), and 37.98% of the newborn were LGA. The body weights (BW) of the SGA 4 weeks post birth had no significant difference from that of the controls, while the perirenal fat weight (FW) and the FW/BW ratio were significantly larger than those of the controls (p<0.01 and p<0.05, respectively); however, the FW/BW of the LGA had no significant difference from that of the controls. Twelve weeks after birth, the BW of both SGA and LGA rats increased significantly compared to the controls (p<0.05 and p<0.01, respectively), and the FW/BW ratios of both were significantly larger than that of the controls (p<0.01). For the SGA rats 4 weeks post birth, the insulin and leptin level increased significantly (both p<0.05), while the ISI decreased significantly (p<0.05), with the occurrence of insulin resistance. For both SGA and LGA 12 weeks post birth, the insulin and leptin level significantly increased (both p<0.01). CONCLUSION: Abnormal nutrition during pregnancy could lead to abnormal birth weight, and both low and high birth weight could cause abdominal obesity as well as insulin and leptin resistance in adulthood, although through different mechanisms.

Brain Structural Networks in Mouse Exposed to Chronic Maternal Undernutrition.

Brain structural connectivity is known to be altered in cases of intrauterine growth restriction and premature birth, although the specific effect of maternal nutritional restriction, a common burden in human populations, has not been assessed yet. Here we analyze the effects of maternal undernutrition during pregnancy and lactation by establishing three experimental groups of female mice divided according to their diet: control (Co), moderate calorie-protein restriction (MCP) and severe protein restriction (SP). Nutritionally restricted dams gained relatively less weight during pregnancy and the body weight of the offspring was also affected by maternal undernutrition, showing global growth restriction. We performed magnetic resonance imaging (MRI) of the offspring's brains after weaning and analyzed their connectivity patterns using complex graph theory. In general, changes observed in the MCP group were more subtle than in SP. Results indicated that brain structures were not homogeneously affected by early nutritional stress. In particular, the growth of central brain regions, such as the temporo-parietal cortex, and long integrative myelinated tracts were relatively preserved, while the frequency of short tracts was relatively reduced. We also found a differential effect on network parameters: network degree, clustering, characteristic path length and small-worldness remained mainly unchanged, while the rich-club index was lower in nutritionally restricted animals. Rich-club decrease reflects an impairment in the structure by which brain regions with large number of connections tend to be more densely linked among themselves. Overall, the findings presented here support the hypothesis that chronic nutritional stress produces long-term changes in brain structural connectivity.

The effects of acute nutrient restriction in the mid-gestational ewe on maternal and fetal nutrient status, the expression of placental growth factors and fetal growth.

This study explores the hypothesis that acute under-nutrition in mid-gestation reduces maternal and fetal nutrient status and affects the expression of specific regulators of placental growth and function. Welsh Mountain ewes were fed a concentrate diet plus wheat straw to provide 100% of their maintenance requirements. The concentrate ration of nutrient restricted (NR) ewes was reduced from day (d) 83 of gestation and withdrawn from d85 to d90. At d90, half the ewes (NR m = 7, control n = 8) were euthanased. The remainder (NR n = 9, control n = 9) were fed their maintenance diet until slaughter at d135. Maternal plasma insulin and IGF-I concentrations decreased during nutrient restriction and NEFA concentrations increased. Fetal IGF-I and insulin concentrations were unaltered by maternal diet. Placental VEGF mRNA expression was reduced at d90 (P < 0.05). IGFBP-3 and IGFBP-2 mRNA expression was reduced at d90 (P < 0.05) and d135 (P < 0.05), respectively. Placental weight was significantly lower in NR ewes at d90 (P < 0.05) and the distribution of placentomes shifted towards the everted phenotype at d135 (P < 0.05). Reduced thoracic girth and uterine fluid volume at d90 (P < 0.05) and decreased fetal lung weight at d90 (P < 0.05) and d135 (P < 0.05) suggest spatial limitation of lung expansion. In summary, acute NR in mid-gestation reduced anabolic drive and mobilised lipid stores in the maternal compartment, whilst fetal nutrient status was maintained. This was accompanied by changes in placental VEGF and IGFBP expression. The growth of the fetal lung appears to have been compromised and this may have adverse consequences for subsequent neonatal respiratory function.