Early Postnatal Growth Restriction Research Articles

An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth.

Postnatal bone growth involves a dramatic increase in length and girth. Intriguingly, this period of growth is independent of growth hormone and the underlying mechanism is poorly understood. Recently, an IGF2 mutation was identified in humans with early postnatal growth restriction. Here, we show that IGF2 is essential for longitudinal and appositional murine postnatal bone development, which involves proper timing of chondrocyte maturation and perichondrial cell differentiation and survival. Importantly, the Igf2 null mouse model does not represent a simple delay of growth but instead uncoordinated growth plate development. Furthermore, biochemical and two-photon imaging analyses identified elevated and imbalanced glucose metabolism in the Igf2 null mouse. Attenuation of glycolysis rescued the mutant phenotype of premature cartilage maturation, thereby indicating that IGF2 controls bone growth by regulating glucose metabolism in chondrocytes. This work links glucose metabolism with cartilage development and provides insight into the fundamental understanding of human growth abnormalities.

Effects of postnatal growth restriction and subsequent catch-up growth on neurodevelopment and glucose homeostasis in rats.

BackgroundThere is increasing evidence that poor growth of preterm infants is a risk factor for poor long-term development, while the effects of early postnatal growth restriction are not well known. We utilized a rat model to examine the consequences of different patterns of postnatal growth and hypothesized that early growth failure leads to impaired development and insulin resistance. Rat pups were separated at birth into normal (N, n = 10) or restricted intake (R, n = 16) litters. At d11, R pups were re-randomized into litters of 6 (R-6), 10 (R-10) or 16 (R-16) pups/dam. N pups remained in litters of 10 pups/dam (N-10). Memory and learning were examined through T-maze test. Insulin sensitivity was measured by i.p. insulin tolerance test and glucose tolerance test.ResultsBy d10, N pups weighed 20 % more than R pups (p < 0.001). By d15, the R-6 group caught up to the N-10 group in weight, the R-10 group showed partial catch-up growth and the R-16 group showed no catch-up growth. All R groups showed poorer scores in developmental testing when compared with the N-10 group during T-Maze test (p < 0.05). Although R-16 were more insulin sensitive than R-6 and R-10, all R groups were more glucose tolerant than N-10.ConclusionIn rats, differences in postnatal growth restriction leads to changes in development and in insulin sensitivity. These results may contribute to better elucidating the causes of poor developmental outcomes in human preterm infants.

Effects of early postnatal growth restriction and subsequent catch-up growth on body composition, insulin sensitivity, and behavior in neonatal rats

Early postnatal growth retardation with subsequent catch-up growth is common in preterm infants. We describe a model of ex utero (postnatal) growth retardation followed by varying degrees of catch-up growth in the neonatal rat. Newborn CD rat pups were randomized to litters of 10 (NN, normal then normal intake) or 16 (R, restricted intake). On day 10, R pups were further randomized to litters of 6 (RC, restricted then catch-up intake), 10 (RN, restricted then normal intake), or 16 (RR, restricted then restricted intake). Body weight, body composition, insulin sensitivity, biochemistry, and learning (passive avoidance test) were assessed. Growth was significantly lower in the R than the NN group. Subsequently, the RC group caught up with the NN group but had higher fat mass; the RN group showed partial catch-up but body composition similar to that of the NN group. Insulin sensitivity did not differ between groups. Learning behavior was significantly better in the NN than the three R groups, and in the RC group than the RR or RN groups. Early postnatal growth retardation is associated with poorer medium-term growth and poorer developmental outcome. Increased catch-up growth is associated with improved developmental outcome but with increased body adiposity, without any significant effect on glucose homeostasis.

Effects of early growth restriction on development and insulin sensitivity in rats

There is increasing evidence that poor growth of preterm infants is a risk factor for poor long‐term development, while the effects of early postnatal growth restriction are not well known. We utilized a rat model to examine consequences of different patterns of postnatal growth and hypothesize that early growth failure leads to impaired development and insulin resistance. Rat pups were separated at birth into normal (N, n = 10) or restricted intake (R, n = 16) litters. At d11 R pups were re‐randomized into litters of 6 (RC; R/catch‐up), 10 (RN; R/normal) or 16 (RR; R/restricted). Pups were weaned at d21. Animals underwent developmental and behavioral tests, including open field maze, T‐Maze and passive avoidance. Insulin sensitivity was measured by i.p. insulin stress test (IPIST) and glucose tolerance test (IPGTT). By d10, N pups weighed 20% more than R pups (p&lt;0.001). By d15, RC caught up to NN pups, RN showed partial catch‐up and RR showed no catch‐up. RR and RC groups showed less explorative behavior during developmental testing3. Further, there was evidence of learning in NN pups during T‐Maze and passive avoidance tests3. Though NN and RR were most insulin sensitive, all R groups were more glucose tolerant compared to NN. In rats, early postnatal growth restriction leads to abnormal development and insulin sensitivity. This “double hit” paradigm may contribute to poor developmental outcomes in preterms.Grant Funding Source: UC Davis Department of Pediatrics

The Intensity of IUGR-Induced Transcriptome Deregulations Is Inversely Correlated with the Onset of Organ Function in a Rat Model

A low-protein diet applied during pregnancy in the rat results in intrauterine growth restricted (IUGR) fetuses. In humans, IUGR is associated with increased perinatal morbidity, higher incidence of neuro-developmental defects and increased risk of adult metabolic anomalies, such as diabetes and cardiovascular disease. Development and function of many organs are affected by environmental conditions such as those inducing fetal and early postnatal growth restriction. This phenomenon, termed “fetal programming” has been studied unconnectedly in some organs, but very few studies (if any) have investigated at the same time several organs, on a more comparative basis. However, it is quite probable that IUGR affects differentially most organ systems, with possible persistent changes in gene expression. In this study we address transcriptional alterations induced by IUGR in a multi-organ perspective, by systematic analysis of 20-days rat fetuses. We show that (1) expressional alterations are apparently stronger in organs functioning late in foetal or postnatal life than in organs that are functioning early (2) hierarchical classification of the deregulations put together kidney and placenta in one cluster, liver, lungs and heart in another; (3) the epigenetic machinery is set up especially in the placenta, while its alterations are rather mild in other organs; (4) the genes appear deregulated in chromosome clusters; (5) the altered expression cascades varies from organ to organ, with noticeably a very significant modification of the complement and coagulation cascades in the kidney; (6) we found a significant increase in TF binding site for HNF4 proteins specifically for liver genes that are down-regulated in IUGR, suggesting that this decrease is achieved through the action of HNF transcription factors, that are themselves transcriptionnally induced in the liver by IUGR (x 1.84 fold). Altogether, our study suggests that a combination of tissue-specific mechanisms contributes to bring about tissue-driven modifications of gene cascades. The question of these cascades being activated to adapt the organ to harsh environmental condition, or as an endpoint consequence is still raised.

Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats

Impaired growth in utero predicts a low nephron number and high blood pressure later in life as does slowed or accelerated growth after a normal birth weight. We measured the effects of early postnatal growth restriction, with or without prenatal growth restriction, on blood pressure and nephron number in male rat offspring. Bilateral uterine artery and vein ligation were performed to induce uteroplacental insufficiency (Restricted) on day 18 of pregnancy. Postnatal growth restriction was induced in a subset of sham operated control animals by reducing the number of pups at birth to that of the Restricted group (Reduced Litter). Compared to Controls, Restricted pups were born smaller while Reduced Litter pups weighed less by postnatal day 3 and both groups remained lighter throughout lactation. By 10 weeks of age all animals were of similar weight but the Reduced Litter rats had elevated blood pressure. At 22 weeks, Restricted but not Reduced Litter offspring were smaller and the blood pressure was increased in both groups. Restricted and Reduced Litter groups had fewer glomeruli and greater left ventricular mass than Controls. These results suggest that restriction of both perinatal and early postnatal growth increase blood pressure in male offspring. This study also demonstrates that the early postnatal period is a critical time for nephron endowment in the rat.

Extrauterine growth restriction in very‐low‐birthweight infants

Postnatal growth failure of very‐low‐birthweight (VLBW) infants may result from a complex interaction of genetic and environmental factors, including inadequate nutrition, morbidities affecting nutrient requirements, endocrine abnormalities and treatments. Among VLBW infants, those small for gestational age (SGA) at birth and those with postnatal growth restriction at the time of discharge are at higher risk of later growth failure and long‐term consequences. Nutritional intervention with an “aggressive nutrition” during the first weeks of life may be able to minimize the interruption of nutrients that occurs at birth, and reduce as much as possible the incidence of growth restriction at the time of discharge and later. Even though aggressive parenteral and enteral nutrition appear to be effective and safe in VLBW infants, further evaluations of their long‐term effect on growth and health consequences are needed. Several studies evaluating the effect of enriched nutrient formulas after hospital discharge on growth and neurodevelopment have produced conflicting results, whereas the potential deleterious long‐term effects of prolonged use of high protein and/or of later catch‐up growth have been questioned. In contrast, recent data seem to indicate that the use of human milk after hospital discharge could be the most beneficial diet for subsequent health and development. Conclusion: VLBW infants SGA at birth and those with early postnatal growth restriction are at high risk of later growth failure and long‐term consequences. Therefore, the first objective of early nutrition should be to reduce the incidence of growth restriction at the time of discharge. Further studies on VLBW infants to evaluate the safety and beneficial effects of prolonged dietary manipulation during the first year of life are needed.

Extrauterine growth restriction in very-low-birthweight infants

Postnatal growth failure of very-low-birthweight (VLBW) infants may result from a complex interaction of genetic and environmental factors, including inadequate nutrition, morbidities affecting nutrient requirements, endocrine abnormalities and treatments. Among VLBW infants, those small for gestational age (SGA) at birth and those with postnatal growth restriction at the time of discharge are at higher risk of later growth failure and long-term consequences. Nutritional intervention with an "aggressive nutrition" during the first weeks of life may be able to minimize the interruption of nutrients that occurs at birth, and reduce as much as possible the incidence of growth restriction at the time of discharge and later. Even though aggressive parenteral and enteral nutrition appear to be effective and safe in VLBW infants, further evaluations of their long-term effect on growth and health consequences are needed. Several studies evaluating the effect of enriched nutrient formulas after hospital discharge on growth and neurodevelopment have produced conflicting results, whereas the potential deleterious long-term effects of prolonged use of high protein and/or of later catch-up growth have been questioned. In contrast, recent data seem to indicate that the use of human milk after hospital discharge could be the most beneficial diet for subsequent health and development. VLBW infants SGA at birth and those with early postnatal growth restriction are at high risk of later growth failure and long-term consequences. Therefore, the first objective of early nutrition should be to reduce the incidence of growth restriction at the time of discharge. Further studies on VLBW infants to evaluate the safety and beneficial effects of prolonged dietary manipulation during the first year of life are needed.

Reply to Comment on: Hales CN, Ozanne SE (2003) For Debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure

Reply to Comment on: Hales CN, Ozanne SE (2003) For Debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure

For debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure.

We review the progress in testing the thrifty phenotype hypothesis. Many human epidemiological studies both by ourselves and others have confirmed and extended the original observations on which the hypothesis was based. We are not aware of any contradictory findings and we emphasise the strength of the association between birth weight and the subsequent development of the metabolic syndrome. We have worked extensively experimentally to test the hypothesis in a rat model in which pregnant and/or lactating dams are fed a diet moderately restricted in proteins. The range of programming effects that we have discovered in this example of fetal and early postnatal growth restriction is listed and includes changes in hormone receptors, signalling molecules and regulatory enzymes. We have shown the model to develop diabetes, the metabolic syndrome and signs of premature renal failure. We summarise these and other similarities between the phenotype of this model and human Type 2 diabetes and the metabolic syndrome. The number of insults during early development which can lead to a similar outcome is discussed and the suggestion is made that the early life response to stress is limited in its flexibility with outcomes including ageing and decreased longevity. Our preliminary results indicate that some MODY genes could suggest pathways whereby the changes occur and that epigenetic changes during development are involved. We conclude that the way is now clear to discover early human markers of programming by early life growth restriction and to use these to devise strategies for the prevention of Type 2 diabetes.

Effects of intrauterine and early postnatal growth restriction on hypothalamic somatostatin gene expression in the rat.

In the human, intrauterine growth retardation (IUGR) can result in persistent postnatal growth failure, which may be attributable, in part, to abnormal GH secretion. Whether putative alterations in GH secretion are the result of abnormalities intrinsic to the pituitary or reflect changes in the production of GH-releasing hormone or somatostatin (SS) is unknown. We tested the hypothesis that growth failure associated with IUGR or early postnatal food restriction (FR) is caused by a central defect in hypothalamic SS gene expression. Both models displayed persistent growth failure postnatally without any catch-up growth. We measured levels of SS mRNA levels in rats experimentally subjected to IUGR or FR. SS mRNA levels were measured by semiquantitative in situ hybridization throughout development. Levels of SS mRNA in the periventricular nucleus were significantly higher in both male and female IUGR rats in the juvenile and adult stages compared with matched controls (p < or = 0.05). FR was associated with higher SS mRNA levels only in neonatal female rats (p < or = 0.05). These results suggest that intrauterine malnutrition induces a persistent increase in the expression of SS mRNA in the periventricular nucleus, whereas early postnatal FR results in only a transient increase in SS gene expression. Because IGF-I levels were normal in juvenile IUGR and FR rats, central dysregulation of SS neurons does not appear to be the cause of early postnatal growth failure in either model. However, these observations are consistent with the hypothesis that nutritional stress at critical times during development can have persistent and potentially irreversible effects on organ function.