Nutritional Insult Research Articles

Post‐infant linear growth is associated with cognitive achievement of 8y‐olds in Ethiopia, India, Peru and Vietnam

Resource allocations for nutrition programs are often based on the assumption that opportunities for long‐term physical and cognitive development close after 2 y. However, cognitive deficits from linear growth failure may be reversible. We used data from Young Lives which includes ~8000 children at 1, 5 and 8 y of age in Ethiopia, India, Peru and Vietnam. We used regression analysis to examine associations between post‐infancy improvement in height not predicted by prior length (unpredicted growth) and cognitive achievement at 8 y. HAZ at 1 y was associated with higher cognitive achievement for all 4 countries and with schooling outcomes (except preschool attendance in Vietnam). In adjusted models, unpredicted change in HAZ from 1 to 8 y was significantly associated with higher scores on standardized tests of math in Ethiopia and India (coefficients of .504 and .509, respectively) and vocabulary (in Ethiopia, India and Peru, 3.079, 2.020, .930, respectively) and appropriate age for grade (.821, .848, .834 and .812 in Ethiopia, India, Peru and Vietnam). We believe this to be the first study to examine the relationship between post‐infancy unpredicted growth and medium‐term child development outcomes. Our results reinforce the gains from addressing nutritional insults not only during infancy but throughout childhood.

Fetal programming of CVD and renal disease: animal models and mechanistic considerations

The developmental origins of health and disease hypothesis postulates that exposure to a less than optimal maternal environment during fetal development programmes physiological function, and determines risk of disease in adult life. Much evidence of such programming comes from retrospective epidemiological cohorts, which demonstrate associations between birth anthropometry and non-communicable diseases of adulthood. The assertion that variation in maternal nutrition drives these associations is supported by studies using animal models, which demonstrate that maternal under- or over-nutrition during pregnancy can programme offspring development. Typically, the offspring of animals that are undernourished in pregnancy exhibit a relatively narrow range of physiological phenotypes that includes higher blood pressure, glucose intolerance, renal insufficiency and increased adiposity. The observation that common phenotypes arise from very diverse maternal nutritional insults has led to the proposal that programming is driven by a small number of mechanistic processes. The remodelling of tissues during development as a consequence of maternal nutritional status being signalled by endocrine imbalance or key nutrients limiting processes in the fetus may lead to organs having irreversibly altered structures that may limit their function with ageing. It has been proposed that the maternal diet may impact upon epigenetic marks that determine gene expression in fetal tissues, and this may be an important mechanism connecting maternal nutrient intakes to long-term programming of offspring phenotype. The objective for this review is to provide an overview of the mechanistic basis of fetal programming, demonstrating the critical role of animal models as tools for the investigation of programming phenomena.

Effects of folate depletion in utero and a high fat diet post-weaning on DNA methylation in the adult mouse small intestine

Increasing evidence from animal studies shows that nutritional insults during development can lead to adverse health in later life. Altered patterns of DNA methylation is a potential mechanism for this programming effect because when DNA is methylated, gene expression is usually repressed. Folate is a major methyl donor so folate depletion in early life may affect DNA methylation and gene expression, leading to increased risk of disease throughout life (1,2) . We have reported that maternal folate depletion influences methylation in the fetal mouse gut (3) . Here we investigated the effects on adult offspring of maternal folate depletion and/or high dietary fat intake post-weaning on gene-specific methylation in the mouse proximal small intestine (SI). Female C57BL/6J mice were randomly assigned to folate-adequate (FA, 2mg/kg) or folate-depleted (FD, 0.4mg/kg) diets 4 weeks prior to mating and assigned diets were maintained during pregnancy and lactation. At weaning, offspring were randomised to a low fat (LF, 5%) or a high fat (HF, 20%) diet. Allocated diets were continued for 6 months when proximal SI samples were collected and snap frozen. DNA was extracted and gene-specific DNA methylation was quantified at ten loci within 6 genes (Esr1, Igf2-DMR1, Slc39a4CGI1 & -CGI2, p16, Obfc2a-amp1, -amp2 & -amp3, and Ppm1k-amp1 & -amp2) by Pyrosequencing. There were no significant effects of maternal folate supply on methylation at any of the loci investigated (n = 24 for FA, n = 24 for FD diet, ANOVA, p >0.05). However, as summarised in the table, methylation at all 9 CpGs and overall mean methylation across all nine CpGs in Slc39a4-CGI1 was significantly lower in DNA from mice fed the HF diet (n = 24 for LF, n = 24 for HF diet, ANOVA, p <0.05). Conversely, methylation at CpGs 3, 4, 5 and mean methylation across all nine CpGs at Obfc2a-amp1, CpGs 1, 4, 6, and overall mean across all nine CpGs at Obfc2a-amp2 were higher in the HF group. Similarly, higher methylation was found at CpGs 2, 4 and mean methylation across all five CpGs in p16; CpGs 1, 2, 4 and overall mean across all four CpGs in Ppm1k-amp1, and CpGs 2, 5, 7 and mean methylation across all seven CpGs in Ppm1k-amp2 in the HF group (ANOVA, p <0.05).

Dynamic changes in digestive capability may contribute to compensatory growth following a nutritional insult in newly weaned pigs1

We have previously demonstrated that feeding low complexity diets (LOW) compromises growth performance of pigs during the first 3 wk after weaning and induces compensatory growth and improved feed efficiency thereafter. A study was undertaken to explore physiological mechanisms involved in compensatory growth following a nutritional insult. Fifty-six pigs were weaned at 21 ± 2 d of age and fed high complexity diets (HIGH) for 6 wk. All pigs received the same grower diet thereafter. Pigs were killed at weeks 2, 4, and 8 after weaning and proximal jejunum and distal ileum were sampled for evaluation of histology and enzyme activity. In the proximal jejunum, villus height was lower (P = 0.03) at week 2 in pigs on LOW than HIGH but not different at week 4. There was no effect of diet on crypt depth; villus height:crypt depth ratio increased (P = 0.02) from week 2 to week 4 in pigs on LOW but was not changed in pigs on HIGH. Diet did not impact gut morphology at the distal ileum. Enzyme activity was lowest (P < 0.05) at week 2 for sucrase and aminopeptidase N (APN) and lowest (P < 0.06) at week 8 for lactase. Sucrase activity was numerically higher at week 4 in pigs fed LOW but numerically higher at week 8 in pigs fed HIGH. Lactase and APN activity were not affected by diet. Compensatory growth observed in pigs following a nutritional insult after weaning may be due in part to improved digestive capability.

Early-age feed restriction affects viability and gene expression of satellite cells isolated from the gastrocnemius muscle of broiler chicks

BackgroundMuscle growth depends on the fusion of proliferate satellite cells to existing myofibers. We reported previously that 0–14 day intermittent feeding led to persistent retardation in myofiber hypertrophy. However, how satellite cells respond to such nutritional insult has not been adequately elucidated.ResultsOne-day-old broiler chicks were allocated to control (Con, ad libitum feeding), intermittent feeding (IF, feed provided on alternate days) and re-feeding (RF, 2 days ad libitum feeding after 12 days of intermittent feeding) groups. Chickens were killed on Day 15 and satellite cells were isolated. When cultured, satellite cells from the IF group demonstrated significant retardation in proliferation and differentiation potential, while RF partly restored the proliferation rate and differentiation potential of the satellite cells. Significant up-regulation of insulin like growth factor I receptor (IGF-IR) (P<0.05) and thyroid hormone receptor α (TRα) (P<0.05), and down-regulation of growth hormone receptor (GHR) (P<0.01) and IGF-I (P<0.01) mRNA expression was observed in freshly isolated IF satellite cells when compared with Con cells. In RF cells, the mRNA expression of IGF-I was higher (P<0.05) and of TRα was lower (P<0.01) than in IF cells, suggesting that RF restored the mRNA expression of TRα and IGF-I, but not of GHR and IGF-IR. The Bax/Bcl-2 ratio tended to increase in the IF group, which was reversed in the RF group (P<0.05), indicating that RF reduced the pro-apoptotic influence of IF. Moreover, no significant effect of T3 was detected on cell survival in IF cells compared with Con (P<0.001) or RF (P<0.05) cells.ConclusionsThese data suggest that early-age feed restriction inhibits the proliferation and differentiation of satellite cells, induces changes in mRNA expression of the GH/IGF-I and thyroid hormone receptors in satellite cells, as well as blunted sensitivity of satellite cells to T3, and that RF partially reverses these effects. Thus, a moderate nutritional strategy for feed restriction should be chosen in early chick rearing systems.

Processes Underlying the Nutritional Programming of Embryonic Development by Iron Deficiency in the Rat

Poor iron status is a global health issue, affecting two thirds of the world population to some degree. It is a particular problem among pregnant women, in both developed and developing countries. Feeding pregnant rats a diet deficient in iron is associated with both hypertension and reduced nephron endowment in adult male offspring. However, the mechanistic pathway leading from iron deficiency to fetal kidney development remains elusive. This study aimed to establish the underlying processes associated with iron deficiency by assessing gene and protein expression changes in the rat embryo, focussing on the responses occurring at the time of the nutritional insult. Analysis of microarray data showed that iron deficiency in utero resulted in the significant up-regulation of 979 genes and down-regulation of 1545 genes in male rat embryos (d13). Affected processes associated with these genes included the initiation of mitosis, BAD-mediated apoptosis, the assembly of RNA polymerase II preinitiation complexes and WNT signalling. Proteomic analyses highlighted 7 proteins demonstrating significant up-regulation with iron deficiency and the down-regulation of 11 proteins. The main functions of these key proteins included cell proliferation, protein transport and folding, cytoskeletal remodelling and the proteasome complex. In line with our recent work, which identified the perturbation of the proteasome complex as a generalised response to in utero malnutrition, we propose that iron deficiency alone leads to a more specific failure in correct protein folding and transport. Such an imbalance in this delicate quality-control system can lead to cellular dysfunction and apoptosis. Therefore these findings offer an insight into the underlying mechanisms associated with the development of the embryo during conditions of poor iron status, and its health in adult life.

Fructose consumption during pregnancy and lactation induces fatty liver and glucose intolerance in rats

Nutritional insults during pregnancy and lactation are health risks for mother and offspring. Both fructose (FR) and low-protein (LP) diets are linked to hepatic steatosis and insulin resistance in nonpregnant animals. We hypothesized that dietary FR or LP intake during pregnancy may exacerbate the already compromised glucose homeostasis to induce gestational diabetes and fatty liver. Therefore, we investigated and compared the effects of LP or FR intake on hepatic steatosis and insulin resistance in unmated controls (CTs) and pregnant and lactating rats. Sprague-Dawley rats were fed a CT, or a 63% FR, or an 8% LP diet. Glucose tolerance test at day 17 of the study revealed greater (P < .05) blood glucose at 10 (75.6 mg/dL vs 64.0 ± 4.8 mg/dL) minutes and 20 (72.4 mg/dL vs 58.6 ± 4.0 mg/dL) minutes after glucose dose and greater area under the curve (4302.3 mg∙dL(-1)∙min(-1) vs 3763.4 ± 263.6 mg∙dL(-1)∙min(-1)) for FR-fed dams compared with CT-fed dams. The rats were euthanized at 21 days postpartum. Both the FR- and LP-fed dams had enlarged (P < .05) livers (9.3%, 7.1% body weight vs 4.8% ± 0.2% body weight) and elevated (P < .05) liver triacylglycerol (216.0, 130.0 mg/g vs 19.9 ± 12.6 mg/g liver weight) compared with CT-fed dams. Fructose induced fatty liver and glucose intolerance in pregnant and lactating rats, but not unmated CT rats. The data demonstrate a unique physiological status response to diet resulting in the development of gestational diabetes coupled with hepatic steatosis in FR-fed dams, which is more severe than an LP diet.

Maternal high-fat intake during pregnancy programs metabolic-syndrome-related phenotypes through liver mitochondrial DNA copy number and transcriptional activity of liver PPARGC1A

In this study, we contrasted the hypothesis that maternal diet during pregnancy has an impact on fetal metabolic programming through changes in liver mitochondrial DNA (mtDNA) content and transcriptional activity of Ppargc1a and that these effects are sex specific. MethodsRats were fed either high-fat (HFD) or standard chow diet (SCD) during gestation and lactation. The resulting adult male and female offspring were fed either HFD or SCD for an 18-week period, generating eight experimental groups. ResultsMaternal HFD feeding during pregnancy is associated with a decreased liver mtDNA copy number (P<.008). This effect was independent of the offspring sex or diet, and was significantly associated with fatty liver when dams were fed HFD (P<.05, adjusted by homeostasis model assessment of insulin resistance, HOMA-IR). We also found that maternal HFD feeding results in a male-specific significant reduction of the liver abundance of Ppargc1a mRNA (P<.004), which significantly impacted peripheral insulin resistance. Liver expression of Ppargc1a was inversely correlated with HOMA-IR (R=−0.53, P<.0003). Only male offspring exposed to a chronic metabolic insult in adult life were insulin resistant and hyperleptinemic, and showed abnormal liver and abdominal fat accumulation. Liver abundance of Tfam, Nrf1, Hnf4a, Pepck and Ppparg mRNA was not associated with maternal programming. In conclusion, maternal high-fat diet feeding during pregnancy programs liver mtDNA content and the transcriptional activity of Ppargc1a, which strongly modulates, in a sex-specific manner, glucose homeostasis and organ fat accumulation in adult life after exposure to a nutritional insult.

Intestinal damage in weanling pigs following a nutritional insult is transient

Forty pigs were used to evaluate the long‐term effect of nutritional insult on measures of intestinal development in weanling pigs. Pigs were weaned at 21±2 days of age and fed diets ad libitum containing either high (H) or low (L) quality protein sources for 6 wks. Growth performance was monitored weekly. Pigs were killed at wk 2 and 4. Sections of proximal jejunum and distal ileum were taken for histology and ileal digesta was sampled. Pigs on L had lower (P = 0.002) daily gain in wks 1–3 but not different in wks 4–6 compared to H pigs. Similarly, feed efficiency in pigs on L was lower (P&lt; 0.05) during wks 2–3 but not different in wks 4–6. In the proximal jejunum, villus height was lower (P = 0.03) at wk 2 in pigs on L (356 vs 427 μm) but not different at wk 4 (527 vs 492 μm). There was no difference in crypt depth but villus height:crypt depth ratio increased (P = 0.04) from wk 2 to wk 4 (1.7 vs 2.2) in pigs on L and did not change in pigs on H (2.3 vs 2.5). Pigs on H tended to have a greater (P &lt; 0.17) proportion of proliferating cells in the jejunum at wk 2 and 4. In wk 2, digesta amine concentration was higher (P = 0.06) in pigs on L. Diet quality did not impact gut morphology or cell proliferation at the distal ileum. Low quality protein sources reduced overall growth performance in weanling pigs but the negative effect of protein quality on gut morphology was transient. Recovery in feed utilization in pigs on L was likely due to rapid recovery of intestinal function.

Histoires personnelles et pièges de pauvreté

Résumé Cet article développe une théorie expliquant les raisons pour lesquelles une pauvreté profonde a une forte tendance à persister à travers des générations. L’auteur montre que les coûts de maintenance élevés de la bonne santé physique et émotionnelle, qui sont des manifestations de la complémentarité entre les apports dont les humains ont besoin pour survivre, sont à la base de l’existence de pièges de pauvreté. Ainsi, les atteintes nutritionnelles pendant les premiers stades de la vie d’une personne peuvent avoir des conséquences irréversibles sur sa capacité future à acquérir le capital humain.

Implications of maternal nutrient restriction in transgenerational programming of hypertension and endothelial dysfunction across F1–F3 offspring

AimsAn extensive variety of prenatal insults are associated with an increased incidence of metabolic and cardiovascular disorders in adult life. We previously demonstrated that maternal global nutrient restriction during pregnancy leads to increased blood pressure and endothelial dysfunction in the adult offspring. This study aimed to assess whether prenatal exposure to nutritional insult has transgenerational effects in F2 and F3 offspring. Main methodsFor this, female Wistar rats were randomly divided into two groups on day 1 of pregnancy: a control group fed standard chow ad libitum and a restricted group fed 50% of the ad libitum intake throughout gestation. At delivery, all animals were fed a standard laboratory chow diet. At 11weeks of age, one female and one male from each restricted litter were randomly selected and mated with rats from another restricted litters in order to generate the F2 offspring. The same procedure produced F3 generation. Similarly, the rats in the control group were bred for each generation. Key FindingsOur findings show that the deleterious effects of maternal nutrient restriction to which the F0 mothers were exposed may not be limited to the male first generation. In fact, we found that elevated blood pressure, an impaired vasodilatory response to acetylcholine and alterations in NO production were all transferred to the subsequent males from F2 and F3 generations. SignificanceOur data show that global nutrient restriction during pregnancy results in a specific phenotype that can be passed transgenerationally to a second and third generation.

Early undernutrition induces glucagon resistance and insulin hypersensitivity in the liver of suckling rats

Developing brains are vulnerable to nutritional insults. Early undernutrition alters their structure and neurochemistry, inducing long-term pathological effects whose causal pathways are not well defined. During suckling, the brain uses glucose and ketone bodies as substrates. Milk is a high-fat low-carbohydrate diet, and the liver must maintain high rates of gluconeogenesis and ketogenesis to address the needs of these substrates. Insulin and glucagon play major roles in this adaptation: throughout suckling, their blood concentrations are low and high, respectively, and the liver maintains low insulin sensitivity and increased glucagon responsiveness. We propose that disturbances in the endocrine profile and available plasma substrates along with undernutrition-related changes in brain cortex capacity for ketone utilization may cause further alterations in some brain functions. We explored this hypothesis in 10-day-old suckling rats whose mothers were severely food restricted from the 14th day of gestation. We measured the plasma/serum concentrations of glucose, ketone body, insulin and glucagon, and hepatic insulin and glucagon responses. Undernutrition led to hypoglycemia and hyperketonemia to 84% (P < 0.001) and 144% (P < 0.001) of control values, respectively. Liver responsiveness to insulin and glucagon became increased and reduced, respectively; intraperitoneal glucagon reduced liver glycogen by 90% (P < 0.01) in control and by 35% (P < 0.05) in restricted. Cortical enzymes of ketone utilization remained unchanged, but their carrier proteins were altered: monocarboxylate transporter (MCT) 1 increased: 73 ± 14, controls; 169 ± 20, undernourished (P < 0.01; densitometric units); MCT2 decreased: 103 ± 3, controls; 37 ± 4, undernourished (P < 0.001; densitometric units). All of these changes, coinciding with the brain growth spurt, may cause some harmful effects associated with early undernutrition.

Effects of Prenatal Micronutrient and Early Food Supplementation on Maternal Hemoglobin, Birth Weight, and Infant Mortality Among Children in Bangladesh

Nutritional insult in fetal life and small size at birth are common in low-income countries and are associated with serious health consequences. To test the hypothesis that prenatal multiple micronutrient supplementation (MMS) and an early invitation to food supplementation would increase maternal hemoglobin level and birth weight and decrease infant mortality, and to assess whether a combination of these interventions would further enhance these outcomes. A randomized trial with a factorial design in Matlab, Bangladesh, of 4436 pregnant women, recruited between November 11, 2001, and October 30, 2003, with follow-up until June 23, 2009. Participants were randomized into 6 groups; a double-masked supplementation with capsules of 30 mg of iron and 400 μg of folic acid, 60 mg of iron and 400 μg of folic acid, or MMS containing a daily allowance of 15 micronutrients, including 30 mg of iron and 400 μg of folic acid, was combined with food supplementation (608 kcal 6 days per week) randomized to either early invitation (9 weeks' gestation) or usual invitation (20 weeks' gestation). Maternal hemoglobin level at 30 weeks' gestation, birth weight, and infant mortality. Under 5-year mortality was also assessed. Adjusted maternal hemoglobin level at 30 weeks' gestation was 115.0 g/L (95% CI, 114.4-115.5 g/L), with no significant differences among micronutrient groups. Mean maternal hemoglobin level was lower in the early vs usual invitation groups (114.5 vs 115.4 g/L; difference, -0.9 g/L; 95% CI, -1.7 to -0.1; P = .04). There were 3625 live births out of 4436 pregnancies. Mean birth weight among 3267 singletons was 2694 g (95% CI, 2680-2708 g), with no significant differences among groups. The early invitation with MMS group had an infant mortality rate of 16.8 per 1000 live births vs 44.1 per 1000 live births for usual invitation with 60 mg of iron and 400 μg of folic acid (hazard ratio [HR], 0.38; 95% CI, 0.18-0.78). Early invitation with MMS group had an under 5-year mortality rate of 18 per 1000 live births (54 per 1000 live births for usual invitation with 60 mg of iron and 400 μg of folic acid; HR, 0.34; 95% CI, 0.18-0.65). Usual invitation with MMS group had the highest incidence of spontaneous abortions and the highest infant mortality rate. Among pregnant women in poor communities in Bangladesh, treatment with multiple micronutrients, including iron and folic acid combined with early food supplementation, vs a standard program that included treatment with iron and folic acid and usual food supplementation, resulted in decreased childhood mortality. isrctn.org Identifier: ISRCTN16581394.

Fetal Programming of Body Composition, Obesity, and Metabolic Function: The Role of Intrauterine Stress and Stress Biology

Epidemiological, clinical, physiological, cellular, and molecular evidence suggests that the origins of obesity and metabolic dysfunction can be traced back to intrauterine life and supports an important role for maternal nutrition prior to and during gestation in fetal programming. The elucidation of underlying mechanisms is an area of interest and intense investigation. In this perspectives paper we propose that in addition to maternal nutrition-related processes it may be important to concurrently consider the potential role of intrauterine stress and stress biology. We frame our arguments in the larger context of an evolutionary-developmental perspective that supports roles for both nutrition and stress as key environmental conditions driving natural selection and developmental plasticity. We suggest that intrauterine stress exposure may interact with the nutritional milieu, and that stress biology may represent an underlying mechanism mediating the effects of diverse intrauterine perturbations, including but not limited to maternal nutritional insults (undernutrition and overnutrition), on brain and peripheral targets of programming of body composition, energy balance homeostasis, and metabolic function. We discuss putative maternal-placental-fetal endocrine and immune/inflammatory candidate mechanisms that may underlie the long-term effects of intrauterine stress. We conclude with a commentary of the implications for future research and clinical practice.

Maternal malnutrition programs the endocrine pancreas in progeny

Type 2 diabetes arises when the endocrine pancreas fails to secrete sufficient insulin to cope with metabolic demands resulting from β cell secretory dysfunction, decreased β cell mass, or both. Epidemiologic studies have shown strong relations between poor fetal and early postnatal nutrition and susceptibility to diabetes later in life. Animal models have been established, and studies have shown that a reduction in the availability of nutrients during fetal development programs the endocrine pancreas and insulin-sensitive tissues. We investigated several modes of early malnutrition in rats. Regardless of the type of diet investigated, whether there was a deficit in calories or protein in food or even in the presence of a high-fat diet, malnourished pups were born with a defect in their β cell population, with fewer β cells that did not secrete enough insulin and that were more vulnerable to oxidative stress; such populations of β cells will never completely recover. Despite the similar endpoint, the cellular and physiologic mechanisms that contribute to alterations in β cell mass differ depending on the nature of the nutritional insult. Hormones that are operative during fetal life, such as insulin, insulin-like growth factors, and glucocorticoids; specific molecules, such as taurine; and islet vascularization have been implicated as possible factors in amplifying this defect. The molecular mechanisms responsible for intrauterine programming of β cells are still elusive, but among them the programming of mitochondria may be a strong central candidate.

Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy

Insulin-like growth factor 1 (IGF-1) is known to exert cardioprotective actions. However, it remains unknown if autophagy, a major adaptive response to nutritional stress, contributes to IGF-1-mediated cardioprotection. We subjected cultured neonatal rat cardiomyocytes, as well as live mice, to nutritional stress and assessed cell death and autophagic rates. Nutritional stress induced by serum/glucose deprivation strongly induced autophagy and cell death, and both responses were inhibited by IGF-1. The Akt/mammalian target of rapamycin (mTOR) pathway mediated the effects of IGF-1 upon autophagy. Importantly, starvation also decreased intracellular ATP levels and oxygen consumption leading to AMP-activated protein kinase (AMPK) activation; IGF-1 increased mitochondrial Ca(2+) uptake and mitochondrial respiration in nutrient-starved cells. IGF-1 also rescued ATP levels, reduced AMPK phosphorylation and increased p70(S6K) phosphorylation, which indicates that in addition to Akt/mTOR, IGF-1 inhibits autophagy by the AMPK/mTOR axis. In mice harbouring a liver-specific igf1 deletion, which dramatically reduces IGF-1 plasma levels, AMPK activity and autophagy were increased, and significant heart weight loss was observed in comparison with wild-type starved animals, revealing the importance of IGF-1 in maintaining cardiac adaptability to nutritional insults in vivo. Our data support the cardioprotective actions of IGF-1, which, by rescuing the mitochondrial metabolism and the energetic state of cells, reduces cell death and controls the potentially harmful autophagic response to nutritional challenges. IGF-1, therefore, may prove beneficial to mitigate damage induced by excessive nutrient-related stress, including ischaemic disease in multiple tissues.

A common cause for a common phenotype: The gatekeeper hypothesis in fetal programming

Sub-optimal nutrition during pregnancy has been shown to have long-term effects on the health of offspring in both humans and animals. The most common outcomes of such programming are hypertension, obesity, dyslipidaemia and insulin resistance. This spectrum of disorders, collectively known as metabolic syndrome, appears to be the consequence of nutritional insult during early development, irrespective of the nutritional stress experienced. For example, diets low in protein diet, high in fat, or deficient in iron are all associated with programming of cardiovascular and metabolic disorders when fed during rat pregnancy. In this paper, we hypothesise that the nutritional stresses act on genes or gene pathways common to all of the insults. We have termed these genes and/or gene pathways the “gatekeepers” and hence developed the “gatekeeper hypothesis”. In this paper, we examine the background to the hypothesis and postulate some possible mechanisms or pathways that may constitute programming gatekeepers.

Cell Cycle Regulation and Cytoskeletal Remodelling Are Critical Processes in the Nutritional Programming of Embryonic Development

Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common “gatekeepers” which may drive nutritional programming.Both protein and iron deficiency in utero reduced the nephron complement in adult male Wistar and Rowett Hooded Lister rats (P<0.05). This occurred in the absence of damage to the glomerular ultrastructure. Microarray, proteomic and pathway analyses identified diet-specific and strain-specific gatekeeper genes, proteins and processes which shared a common association with the regulation of the cell cycle, especially the G1/S and G2/M checkpoints, and cytoskeletal remodelling. A cell cycle-specific PCR array confirmed the down-regulation of cyclins with protein restriction and the up-regulation of apoptotic genes with iron deficiency.The timing and experimental design of this study have been carefully controlled to isolate the common molecular mechanisms which may initiate the sequelae of events involved in nutritional programming of embryonic development. We propose that despite differences in the individual genes and proteins affected in each strain and with each diet, the general response to nutrient deficiency in utero is perturbation of the cell cycle, at the level of interaction with the cytoskeleton and the mitotic checkpoints, thereby diminishing control over the integrity of DNA which is allowed to replicate. These findings offer novel insight into the primary causes and mechanisms leading to the pathologies which have been identified by previous programming studies.

Impact of maternal chromium restriction on glucose tolerance, plasma insulin and oxidative stress in WNIN rat offspring

Robust evidence suggests that nutritional insult during fetal development could program the offspring to glucose intolerance, impaired insulin response and insulin resistance (IR). Considering the importance of chromium (Cr) in maintaining carbohydrate metabolism, this study determined the effect of maternal Cr restriction (CrR) on glucose metabolism and plasma insulin in Wistar/NIN (WNIN) rat offspring and the associated biochemical and/or molecular mechanisms. Female, weanling WNIN rats received ad libitum for 12 weeks, a control diet or the same with 65% restriction of Cr and mated with control males. Some of the Cr-restricted dams were rehabilitated from conception or parturition and their pups weaned on to control diet. At the time of weaning, half of the Cr restricted offspring were rehabilitated to control diet while others continued on Cr-restricted diet. Maternal CrR increased fasting plasma glucose, fasting insulin, homeostasis model assessment of IR, and area under the curve of glucose and insulin during oral glucose tolerance test in the offspring. Expression and activity of rate-limiting enzymes of glucose metabolism were comparable among different groups and expression of genes involved in insulin secretion was increased albeit in male offspring whereas antioxidant enzyme activities were decreased in offspring of both genders. Rehabilitation, in general, corrected the changes albeit partially. Maternal dietary CrR induced IR, impaired glucose tolerance in WNIN rat offspring and was associated with increased oxidative stress, which may predispose them to type 2 diabetes in their later life.

Rehydration in acute gastro-enteritis - the value of going rapid and enteral

Acute gastro-enteritis (AGE) is a leading post-neonatal cause of death among South Africa’s children. Almost all these deaths are caused by the consequences of dehydration. Many of these deaths occur in hospitals. AGE is also a significant nutritional insult at a critical time of growth. When the literature on therapy for AGE is reviewed, only four interventions recommend themselves for universal application for uncomplicated disease: rapid rehydration within 4 - 6 hours with hypotonic solutions, preferably via the gut; continuation of breastfeeding throughout the episode; early re-introduction of full-strength feeds; and zinc therapy. This article explores the first of these, but will show how its application enhances the positive effects of feeding on the diarrhoea as well as the child’s nutritional status.