Malnutrition in early life and its neurodevelopmental and cognitive consequences: a scoping review.

The negative impact of stunting and severe underweight on cognitive neurodevelopment of children is well documented; however, the effect of overweight/obesity is still unclear. The 2018 Global Nutrition Report reported that stunting and overweight concurrently affect 189 million children worldwide. As existing reviews discuss undernutrition and overweight/obesity separately, this scoping review aims to document the impact of mild/moderate and severe underweight, stunting, and overweight/obesity among children aged 0-60 months on their cognitive neurodevelopmental trajectories. Twenty-six articles were analysed to extract significant information from literature retrieved from PubMed and Cochrane databases published from 1 January 2009 to 31 October 2019. Length gain is associated with cognitive neurodevelopment in normo-nourished and stunted children aged under 24 months. Among stunted children, it seems that cognitive and neurodevelopmental deficits can potentially be recovered before 8 years of age, particularly in those whose nutritional status has improved. The impact of overweight/obesity on cognitive neurodevelopment appears to be limited to attention, gross motor skills and executive control. Parental education level, birth weight/length, breastfeeding duration, and sanitation level are some identifiable factors that modify the impact of undernutrition and overweight/obesity on cognitive and neurodevelopment. In conclusion, underweight, stunting and overweight/obesity have a significant impact on cognitive neurodevelopment. Multidimensional approaches with various stakeholders should address all issues simultaneously, such as improving sanitation levels, assuring parental job security and adequate social welfare, and providing access to adequate nutrients for catch-up growth among underweight or stunted children and to affordable healthy foods for those who are overweight/obese and from low socio-economic status.

Triennial Growth Symposium: leucine acts as a nutrient signal to stimulate protein synthesis in neonatal pigs.

The postprandial increases in AA and insulin independently stimulate protein synthesis in skeletal muscle of piglets. Leucine is an important mediator of the response to AA. We have shown that the postprandial increase in leucine, but not isoleucine or valine, acutely stimulates muscle protein synthesis in piglets. Leucine increases muscle protein synthesis by modulating the activation of mammalian target of rapamycin (mTOR) complex 1 and signaling components of translation initiation. Leucine increases the phosphorylation of mTOR, 70-kDa ribosomal protein S6 kinase-1, eukaryotic initiation factor (eIF) 4E-binding protein-1, and eIF4G; decreases eIF2α phosphorylation; and increases the association of eIF4E with eIF4G. However, leucine does not affect the upstream activators of mTOR, that is, protein kinase B, adenosine monophosphate-activated protein kinase, and tuberous sclerosis complex 1/2, or the activation of translation elongation regulator, eukaryotic elongation factor 2. The action of leucine can be replicated by α-ketoisocaproate but not by norleucine. Interference by rapamycin with the raptor-mTOR interaction blocks leucine-induced muscle protein synthesis. The acute leucine-induced stimulation of muscle protein synthesis is not maintained for prolonged periods, despite continued activation of mTOR signaling, because circulating AA fall as they are utilized for protein synthesis. However, when circulating AA concentrations are maintained, the leucine-induced stimulation of muscle protein synthesis is maintained for prolonged periods. Thus, leucine acts as a nutrient signal to stimulate translation initiation, but whether this translates into a prolonged increase in protein synthesis depends on the sustained availability of all AA.

Amino acids and insulin are regulators of muscle protein synthesis in neonatal pigs.

The stage of development between birth and weaning in mammals is a period of very rapid growth that is crucial for the long-term well-being of the animal. The rate of protein deposition in neonatal animals is very high because dietary protein is efficiently utilized to increase body protein mass. Our studies in neonatal pigs have shown that this high efficiency of protein deposition is largely due to the marked increase in protein synthesis after feeding, and this response is particularly profound in the skeletal muscle. The enhanced stimulation of muscle protein synthesis in neonates after feeding is independently mediated by the rise in insulin and amino acids and this response declines with age. Intracellular signaling components that respond to the postprandial rise in amino acids and insulin have been identified and their activation has been shown to be elevated in skeletal muscle of neonatal pigs after a meal and to decrease with development. The enhanced activation of these components in the amino acid and insulin signaling pathways in neonatal muscle contributes to the high rate of muscle protein synthesis and rapid gain in skeletal muscle mass in newborn pigs, which are essential determinants of efficient growth during development.

Postnatal ontogeny of skeletal muscle protein synthesis in pigs.

The neonatal period is characterized by rapid growth and elevated rates of synthesis and accretion of skeletal muscle proteins. The fractional rate of muscle protein synthesis is very high at birth and declines rapidly with age. The elevated capacity for muscle protein synthesis in the neonatal pig is driven by the high ribosome content and, together with an increased efficiency of the translation process, promotes accelerated protein synthesis rates. Feeding profoundly stimulates muscle protein synthesis in neonatal pigs and the response decreases with age. The feeding-induced stimulation of muscle protein synthesis is modulated by an enhanced sensitivity to the postprandial increase in insulin and amino acids. The developmental decline in the response to insulin and amino acids parallels a marked decrease in the feeding-induced activation of translation initiation factors that regulate the binding of mRNA to the 40S ribosomal complex. The abundance and activation of many known positive regulators of the nutrient- and insulin-signaling pathways that are involved in translation initiation are high, whereas those of many negative regulators are low in skeletal muscle of younger pigs. Thus, the activation and(or) abundance of the positive regulators, such as the insulin receptor, insulin receptor-substrate-1, phosphoinositide-3 kinase, phosphoinositide-dependent kinase-1, protein kinase B, mammalian target of rapamycin, raptor, ribosomal protein S6 kinase-1, eukaryotic initiation factor (eIF) 4E-binding protein 1, and eIF4E associated with eIF4G, are greater in 7-d-old pigs than in 26-d-old pigs. The activation of negative regulators, including protein tyrosine phosphatase-1B, phosphatase and tensin homologue deleted on chromosome 10, protein phosphatase 2A, and tuberous sclerosis complex 1/2, are lower in 7-d-old pigs than in 26-d-old pigs. Thus, the developmental decline in the stimulation of skeletal muscle protein synthesis by insulin and amino acids is due in part to the developmentally related decrease in the activation of the signaling pathways that lead to translation initiation.

Somatotropin regulation of protein metabolism in pigs.

A primary goal of exogenous somatotropin treatment is to increase lean body mass. This is accomplished, in part, by increasing the efficiency with which dietary amino acids are used for protein deposition. Somatotropin administration also improves protein balance by minimizing the loss of protein during fasting and maximizing the protein gained during meal absorption. Amino acid catabolism is decreased by somatotropin treatment, as indicated by decreases in blood urea nitrogen, urea synthesis, hepatic urea cycle enzyme activity, and amino acid oxidation. Stable isotope tracer/mass transorgan balance studies have recently demonstrated that somatotropin treatment increases protein anabolism in young, growing swine by increasing protein synthesis in the hind limb and portal-drained viscera in the fed state, with little effect on protein degradation. Detailed study of the tissue-specific responses indicates that somatotropin treatment increases protein synthesis in skeletal muscle by increasing the efficiency of the translational process, but only in the fed state. The somatotropin-induced stimulation of skeletal muscle protein synthesis involves mechanisms that enhance the binding of both mRNA and initiator methionyl-tRNA to the 40S ribosomal subunit. Somatotropin increases protein synthesis in the liver in both the fasted and fed states by increasing ribosome number, with no change in translation initiation. Thus, the protein synthetic response to somatotropin treatment is tissue-specific and dependent on nutritional state.

Developmental changes in the feeding-induced activation of the insulin-signaling pathway in neonatal pigs.

In neonatal animals, feeding stimulates skeletal muscle protein synthesis, a response that declines with development. Both the magnitude of the feeding response and its developmental decline can be reproduced by insulin infusion, suggesting that an altered responsiveness to insulin is a primary determinant of the developmental decline in the stimulation of protein synthesis by feeding. In this study, 7- and 26-day-old pigs were either fasted overnight or fed porcine milk after an overnight fast. We examined the abundance and degree of tyrosine phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and IRS-2 in skeletal muscle and, for comparison, liver. We also evaluated the association of IRS-1 and IRS-2 with phosphatidylinositol 3-kinase (PI 3-kinase). The abundance of IR protein in muscle was twofold higher at 7 than at 26 days, but IRS-1 and IRS-2 abundances were similar in muscle of 7- and 26-day-old pigs. The feeding-induced phosphorylations were greater at 7 than at 26 days of age for IR (28- vs. 13-fold), IRS-1 (14- vs. 8-fold), and IRS-2 (21- vs. 12-fold) in muscle. The associations of IRS-1 and IRS-2 with PI 3-kinase were also increased by refeeding to a greater extent at 7 than at 26 days (9- vs. 5-fold and 6- vs. 4-fold, respectively). In liver, the abundance of IR, IRS-1, and IRS-2 was similar at 7 and 26 days of age. Feeding increased the activation of IR, IRS-1, IRS-2, and PI 3-kinase in liver only twofold, and these responses were unaffected by age. Thus our findings demonstrate that the feeding-induced activation of IR, IRS-1, IRS-2, and PI 3-kinase in skeletal muscle decreases with development. Further study is needed to ascertain whether the developmental decline in the feeding-induced activation of early insulin-signaling components contributes to the developmental decline in translation initiation in skeletal muscle.

Localization and expression of BCAT during pregnancy and lactation in the rat mammary gland.

During lactation, branched-chain aminotransferase (BCAT) gene expression increases in the mammary gland. To determine the cell type and whether this induction is present only during lactation, female rats were randomly assigned to one of three experimental groups: pregnancy, lactation, or postweaning. Mammary gland BCAT activity during the first days of pregnancy was similar to that of virgin rats, increasing significantly from day 16 to the last day of pregnancy. Maximal BCAT activity occurred on day 12 of lactation. During postweaning, BCAT activity decreased rapidly to values close to those observed in virgin rats. Analyses by Western and Northern blot revealed that changes in enzyme activity were accompanied by parallel changes in the amount of enzyme and its mRNA. Immunohistochemical studies of the mammary gland showed a progressive increase in mitochondrial BCAT (mBCAT)-specific staining of the epithelial acinar cells during lactation, reaching high levels by day 12. Immunoreactivity decreased rapidly after weaning. There was a significant correlation between total BCAT activity and milk production. These results indicate that the pattern of mBCAT gene expression follows lactogenesis stages I and II and is restricted to the milk-producing epithelial acinar cells. Furthermore, BCAT activity is associated with milk production in the mammary gland during lactation.

Developmental changes in the feeding-induced stimulation of translation initiation in muscle of neonatal pigs.

The rapid gain in skeletal muscle mass in the neonate is associated with a marked elevation in skeletal muscle protein synthesis in response to feeding. The feeding-induced response decreases with development. To determine whether the response to feeding is regulated at the level of translation initiation, the expression, phosphorylation, and function of a number of eukaryotic initiation factors (eIF) were examined. Pigs at 7 and 26 days of age were either fasted overnight or fed porcine milk after an overnight fast. In muscle of 7-day-old pigs, the hyperphosphorylated form of the eIF4E repressor protein, 4E-binding protein 1 (4E-BP1), was undetectable in the fasting state but rose to 60% of total 4E-BP1 after feeding; eIF4E phosphorylation was unaffected by feeding status. The amount of eIF4E in the inactive 4E-BP1. eIF4E complex was reduced by 80%, and the amount of eIF4E in the active eIF4E. eIF4G complex was increased 14-fold in muscle of 7-day-old pigs after feeding. The amount of 70-kDa ribosomal protein S6 (p70(S6)) kinase in the hyperphosphorylated form rose 2.5-fold in muscle of 7-day-old pigs after feeding. Each of these feeding-induced responses was blunted in muscle of 26-day-old pigs. eIF2B activity in muscle was unaffected by feeding status but decreased with development. Feeding produced similar changes in eIF characteristics in liver and muscle; however, the developmental changes in liver were not as apparent as in skeletal muscle. Thus the results demonstrate that the developmental change in the acute stimulation of skeletal muscle protein synthesis by feeding is regulated by the availability of eIF4E for 48S ribosomal complex formation. The results further suggest that the overall developmental decline in skeletal muscle protein synthesis involves regulation by eIF2B.

Feeding stimulates protein synthesis in muscle and liver of neonatal pigs through an mTOR-dependent process.

Protein synthesis is repressed in both skeletal muscle and liver after a short-term fast and is rapidly stimulated in response to feeding. Previous studies in rats and pigs have shown that the feeding-induced stimulation of protein synthesis is associated with activation of the 70-kDa ribosomal protein S6 kinase (S6K1) as well as enhanced binding of eukaryotic initiation factor eIF4E to eIF4G to form the active eIF4F complex. In cells in culture, hormones and nutrients regulate both of these events through a protein kinase termed the mammalian target of rapamycin (mTOR). In the present study, the involvement of mTOR in the feeding-induced stimulation of protein synthesis in skeletal muscle and liver was examined. Pigs at 7 days of age were fasted for 18 h, and then one-half of the animals were fed. In addition, one-half of the animals in each group were administered rapamycin (0.75 mg/kg) 2 h before feeding. The results reveal that treating 18-h fasted pigs with rapamycin, a specific inhibitor of mTOR, before feeding prevented the activation of S6K1 and the changes in eIF4F complex formation observed in skeletal muscle and liver after feeding. Rapamycin also ablated the feeding-induced stimulation of protein synthesis in liver. In contrast, in skeletal muscle, rapamycin attenuated, but did not prevent, the stimulation of protein synthesis in response to feeding. The results suggest that feeding stimulates hepatic protein synthesis through an mTOR-dependent process involving enhanced eIF4F complex formation and activation of S6K1. However, in skeletal muscle, these two processes may account for only part of the stimulation of protein synthesis, and thus additional steps may be involved in the response.

Regulation of branched-chain amino acid metabolism in the lactating rat.

There is evidence that during lactation, uptake of the essential branched-chain amino acids (BCAA) by mammary glands exceeds their output in milk protein. In this study, we have measured the potential of lactating rats to catabolize BCAA. The activity, relative protein and specific mRNA levels of the first two enzymes in the BCAA catabolic pathway, branched-chain aminotransferase (BCAT) and branched-chain alpha-keto acid dehydrogenase (BCKD), were measured in mammary gland, liver and skeletal muscle obtained from rat dams at peak lactation (12 d), from rat dams 24 h after weaning at peak lactation and from age-matched virgin controls. Western analysis showed that the mitochondrial BCATm isoenzyme was found in mammary gland. Comparison of lactating and control rats revealed that tissue BCATm activity, protein and mRNA were at least 10-fold higher in mammary tissue during lactation. Values were 1.3- to 1. 9-fold higher after 24 h of weaning. In mammary gland of lactating rats, the BCKD complex was fully active. In virgin controls and weaning dams, only about 20% of the complex was in the active state. Hypertrophy of the liver and mammary gland during lactation resulted in a 73% increase in total oxidative capacity in lactating rats. The results are consistent with increased expression of the BCATm gene in the mammary gland during lactation, whereas oxidation appears to be regulated primarily by changes in activity state (phosphorylation state) of BCKD.

A molecular model of human branched-chain amino acid metabolism.

To establish an accurate molecular model of human branched-chain amino acid (BCAA) metabolism, the distribution, activity, and expression of the first 2 enzymes in the catabolic pathway--branched-chain-amino-acid aminotransferase (BCAT) and branched-chain alpha-keto acid dehydrogenase (BCKD) complex--were determined in human tissues. The same enzyme activities were measured in rat and African green monkey tissues. Overall, the activities of BCAT and BCKD were higher in rat than in human and monkey tissues; nevertheless, the ratio of the 2 activities was similar in most tissues in the 3 species. Total oxidative capacity was concentrated in skeletal muscle and liver (> 70%) with muscle having a higher proportion of the total in humans and monkeys. In humans, brain (10-20%) and kidney (8-13%) may contribute significantly to whole-body BCAA metabolism. Furthermore, in primates the high ratio of transaminase to oxidative capacity in the entire gastrointestinal tract serves to prevent loss of essential BCAA carbon and raises the possibility that the gastrointestinal tract contributes to the plasma branched-chain alpha-keto acid pool. Quantitative polymerase chain reaction was used to examine expression of human branched-chain alpha-keto acid dehydrogenase kinase (BCKDK), the key enzyme that regulates the activity state of the human BCKD complex and human BCAT isoenzymes. To design the primers for the polymerase chain reaction, human BCKDK was cloned. BCKDK message was found in all human tissues tested, with the highest amount in human muscle. As in rats, there was ubiquitous expression of mitochondrial BCAT, whereas mRNA for the cytosolic enzyme was at or below the limit of detection outside the brain. Finally, the role of BCAA in body nitrogen metabolism is discussed.

Insulin and hydrocortisone, but not triiodothyronine, are required for the differentiation of pig preadipocytes in primary culture.

The objective of this study was to establish optimal conditions for the primary culture of pig preadipocytes. We cultured pig preadipocytes for 10 d and studied the effects of insulin, hydrocortisone, and triiodothyronine (T3) added to serum-free basal medium on differentiation and gene expression of lipoprotein lipase an early marker, and adipsin, a late marker of preadipocyte differentiation. Insulin alone and hydrocortisone alone stimulated a low level of cell differentiation, as indicated by an increase in glycerol-3-phosphate dehydrogenase activity. When added together, insulin and hydrocortisone had a synergistic effect on cell differentiation. When combined with insulin or hydrocortisone, T3 had no effect on cell differentiation, indicating that T3 is not required in porcine preadipocyte culture. Gene expression studies also showed that removal of insulin or hydrocortisone from complete serum-free medium reduced both early and late marker mRNA. As expected, removal of T3 had no effect on the gene expression of early and late marker mRNA. We conclude that insulin and hydrocortisone, but not T3, are required for the differentiation of pig preadipocytes in primary culture.

Effect of retinoic acid on differentiation of cultured pig preadipocytes.

We studied the effect of retinoic acid on the differentiation of cultured porcine preadipocytes. Porcine preadipocytes were cultured in serum-free medium (DME/F12 medium containing 100 nM insulin, 10 micrograms/mL transferrin, and 50 ng/mL hydrocortisone). Addition of increasing amounts of retinoic acid (1 nM to 20 microM) to the medium reduced glycerol-3-phosphate dehydrogenase (GPDH) activity, a late marker of preadipocyte differentiation. At lower concentrations (0.1 to 10 nM), retinoic acid had no effect on the GPDH activity. Addition of retinoic acid (10 microM) for 24 h during the early stage of development (d 1) greatly inhibited the GPDH activity. After the cells were differentiated, however, retinoic acid no longer had any effect. Therefore, retinoic acid was most effective in undifferentiated cells. Following a 24-h exposure of porcine preadipocytes to retinoic acid at d 1, Northern blot analysis showed that there was a decrease in lipoprotein lipase and adipsin mRNA levels. The results suggest that retinoic acid is a potent inhibitor of porcine preadipocyte differentiation in primary culture.

Effect of age on the differentiation of porcine adipose stromal-vascular cells in culture.

Stromal-vascular (S-V) cells isolated from adipose tissue of newborn pigs (NBPC) and mature pigs (MPC) by collagenase digestion were used to evaluate differences in preadipocyte culture and development. Cells were seeded at a density of 3 x 10(4) cells/cm2 on six-well (35-mm) tissue culture plates in 3 mL of DMEM/HAM's F12 medium plus 10% fetal calf serum and cultured at 37 degrees C under a humidified atmosphere of 95% air:5% CO2 for 24 h. Cells were then washed thoroughly in DMEM/HAM's F12 medium without fetal calf serum and maintained in serum free (SF) medium or SF medium supplemented with 2.5% newborn pig serum (NBPS) or mature pig serum (MPS) for 12 d. After 1 d, more NBPC adhered to the culture plates, as indicated by DNA values. After 12 d, protein per culture well was not significantly different, but DNA concentration per well remained higher (P < .05) in cultures of NBPC than in the MPC cultured in the same medium, indicating fewer MPC. Protein:DNA ratios were higher (P < .05) in cultures of MPC regardless of the medium, reflecting larger cell size. More cells containing fat deposits were seen with NBPC in all conditions in comparison with MPC, and more fat was deposited in NBPC in SF than in SF plus NBPS or MPS. The NBPC had higher (P < .05) sn-glycerol-3-phosphate dehydrogenase (GPDH; EC 1.1.1.8) per protein than MPC regardless of the medium. For both cell types, GPDH activity in either serum was less than activity of cells grown in SF.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of serum on differentiation of porcine adipose stromal-vascular cells in primary culture.

1. Serum-containing media without additional hormones failed to support the differentiation of porcine SV cells while hormone-supplemented serum-free medium (ITTC) stimulated differentiation as indicated by higher GPDH specific activity. 2. All sera tested stimulated proliferation and inhibited porcine SV cell differentiation to some degree; fetal calf and rat sera were more inhibitory than calf and pig sera. 3. Morphologically, in serum-free medium porcine SV cells developed into individual adipocytes while in all serum-containing media they formed fat cell clusters. 4. Insulin and hydrocortisone in serum-free medium were important factors in SV cell differentiation while transferrin, T3, and fibroblast growth factor (FGF) were less important.

Effect of antiserum to rat adipocytes on growth and body composition of the rat.

1. Antibody against intact adipocytes was produced in sheep and was capable of binding to intact rat adipocytes using an immunofluorescent assay. An antibody dose level was established and subsequently used in vivo. 2. This study demonstrated inconsistent response of passive immunization procedures with crude antibody against rat adipocytes. Establishment of specific protocols for each antibody preparation would be essential for using this immunological approach in body fat reduction.

Effect of cimaterol on sheep adipose tissue lipid metabolism.

Effects of dietary cimaterol (5 mg/kg) on adipose tissue metabolism of wether lambs were studied. Lipogenesis, lipolysis, fatty acid composition and adipocyte size and number were measured. Cimaterol feeding increased lipogenesis; however, this effect was not statistically significant. Insulin (1,000 microU/ml) stimulated lipogenesis of adipose tissue from control sheep. However, this elevated rate was abolished by in vitro cimaterol. Insulin had no stimulatory effect on lipogenesis in cimaterol-fed sheep. Lipolysis was depressed by cimaterol feeding. However, 10(-4) M cimaterol stimulated lipolysis in the adipose tissue from both control and cimaterol-fed sheep. Insulin inhibited stimulated lipolysis in adipose tissue from control sheep but had no effect on the stimulated lipolysis in cimaterol-fed sheep. Mean adipocyte diameter was smaller (from 74 to 70 microns) and adipocyte size distribution also was changed in the cimaterol-fed sheep. Adipocyte number per gram of tissue was not affected by cimaterol. There was a significant increase in percentage of unsaturated fatty acids in adipose tissue from cimaterol-fed sheep. These results indicate that lipogenic and lipolytic responses to insulin and cimaterol in sheep adipose tissue were altered by cimaterol feeding. The carcass fat content decrease in cimaterol-fed sheep may be attributed to the reduction in adipocyte size.