RESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Conducta Animal , Composición Corporal , Crecimiento , Resistencia a la Insulina , Animales , Animales Recién Nacidos , Femenino , Masculino , RatasRESUMEN
Staple foods, such as rice, can now be enriched in micronutrients through conventional breeding (i.e., biofortification) to enhance dietary intake of vulnerable populations. The objectives of this study were (1) to establish a rapid, high capacity Caco-2 cell model to determine the relative bioavailability of zinc (Zn) from samples of staple food breeding lines for potential use as a guideline for selection/breeding and (2) to determine the relative bioavailability of Zn from conventional rice varieties and one Zn-biofortified type. Polished or undermilled, parboiled rice samples were digested in vitro with pepsin and pH adjustment, and by pancreatic enzymes. Zn uptake from digested samples was measured in Caco-2 cells in culture. A previously validated rat pup model was also used to assess Zn absorption in vivo, using gastric intubation and (65)Zn labeling. Pups were killed after 6 h, and radioactivity in tissues and in small intestine perfusate and cecum-colon contents was used to measure Zn bioavailability. A biofortified rice variety contained substantially more Zn than conventional varieties, with no change in phytate content. Absorbed Zn (µg/g rice) was significantly higher from the new variety in both the in vitro Caco-2 cell model (2.1-fold) and the rat pup model (2.0-fold). Results from the two models were highly correlated, particularly for the polished samples. Biofortification of rice with Zn results in significantly increased Zn uptake in both models. Since results from the Caco-2 cell model correlated well with those from rat pups, this cell model is likely to predict results in human populations and can be used for screening purposes.
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Alimentos Fortificados , Oryza/química , Semillas/química , Zinc/farmacocinética , Animales , Cruzamiento/métodos , Células CACO-2 , Digestión , Humanos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Absorción Intestinal , Pepsina A/metabolismo , Ácido Fítico/análisis , Ratas , Ratas Sprague-Dawley , Semillas/metabolismo , Zinc/análisisRESUMEN
INTRODUCTION: We have previously investigated effects of moderate maternal zinc (Zn) restriction on growth and glucose homeostasis in offspring, but interaction between maternal Zn restriction and postnatal nutrition have not been studied. RESULTS: Weight and serum Zn were lower in ZnD-IN than in ZnC-IN rats at wk 3, but ZnD-AN and ZnD-EN rats had greater weights than respective controls and higher insulin-like growth factor-1 (ZnD-AN) and leptin levels (ZnD-EN). Subsequently, both ZnD-AN and ZnD-EN pups were insulin resistant, and had evidence of elevated serum leptin and depressed insulin receptor phosphorylation with gender-specific differences up to 15 weeks. DISCUSSION: Maternal Zn restriction interacted with postnatal nutritional status, resulting in divergent effects on weight gain and insulin resistance. Interaction between potential effects of fetal Zn restriction and food availability postnatally may be one factor responsible for later metabolic derangements. METHODS: Rats were fed Zn restricted (ZnD, 7 µg/g) or control (ZnC, 25 µg/g) diets ad libitum from 3 wk pre-conception to 3 wk post-parturition. Postnatally, litters were culled to 13 (IN, inadequate nutrition), 7 (AN, adequate nutrition), and 4 (EN, excess nutrition) pups/dam, respectively, and nursed by their original mothers. Postweaning, pups were fed rodent diet ad libitum. Tests to assess insulin resistance were performed subsequently.
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Animales Recién Nacidos/crecimiento & desarrollo , Glucosa/metabolismo , Homeostasis/fisiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Zinc/deficiencia , Animales , Animales Recién Nacidos/metabolismo , Péptido C/sangre , Femenino , Insulina/sangre , Resistencia a la Insulina/fisiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/sangre , Masculino , Modelos Animales , Estado Nutricional , Embarazo , Ratas , Ratas Sprague-Dawley , Caracteres Sexuales , Zinc/sangreRESUMEN
We previously showed that zinc (Zn) supplementation of Zn-adequate dams induced immunosuppressive effects that persist in the offspring after weaning. We investigated whether the immunosuppressive effects were due to in utero exposure and/or mediated via milk using a cross-fostering design. Pregnant rats with adequate Zn nutriture were supplemented with either Zn (1.5 mg Zn in 10% sucrose) or placebo (10% sucrose) during pregnancy (3 times/wk). At postnatal d 3, 4 pups of Zn-supplemented dams (Zn-P) were exchanged with 4 of placebo-supplemented dams (P-Zn). The remaining pups continued with their biological mothers (Zn-Zn and P-P). Pups were orally immunized with dinitrophenol ovalbumin-BSA and/or cholera toxin B subunit (CTB), and serum Zn concentrations and cellular and humoral responses were assessed. Pups of Zn-supplemented dams had higher serum Zn when fostered either by placebo- or Zn-supplemented dams compared to pups of placebo-supplemented dams (P < 0.01). Postnatal Zn exposure reduced the number of Peyer's patches in both the Zn-Zn and P-Zn groups (P < 0.01). Prenatal Zn exposure suppressed CTB- (P = 0.05) and BSA-specific proliferation response of Peyer's Patch lymphocytes (P = 0.07). Prenatal Zn exposure effects on the splenocyte cytokine response were differently influenced by fostering mothers' Zn status. Antigen presenting cell (APC) activity of splenocytes was lower in the Zn-Zn group than in the P-P group (P < 0.08). In conclusion, prenatal Zn exposure increases serum Zn levels in pups and suppresses antigen-specific proliferation and antibody responses and APC function, whereas postnatal exposure may suppress the mucosal immune reservoir.
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Suplementos Dietéticos , Efectos Tardíos de la Exposición Prenatal , Zinc/administración & dosificación , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Peso Corporal , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Tamaño de los Órganos , Embarazo , Ratas , Espectrofotometría Atómica , Zinc/análisisRESUMEN
Interactions among zinc (Zn), insulin, and glucose metabolism are complex. Maternal Zn deficiency affects maternal carbohydrate metabolism, but the mechanisms underlying changes in glucose homeostasis of offspring are not well understood. Rats consumed Zn-deficient (ZnD; 7 microg/g) or control (ZnC; 25 microg/g) diets ad libitum from 3 wk preconception to 21 d postparturition. Litters were culled to 7 pups/dam postnatally and pups were allowed to nurse their original mothers; after weaning, pups were fed nonpurified diet. Insulin and glucose tolerance tests were performed on the pups at wk 5 and 10. Although there was no difference in birth weight between groups, ZnD pups weighed significantly more than controls by d 10 (+5%) and 20 (+10%). Both blood glucose and serum insulin-like growth factor (IGF-1) concentrations at wk 3 were significantly higher in ZnD pups than in controls. Both male and female ZnD rats were less sensitive to insulin and glucose stimulation than controls at wk 5 and 10. At wk 15, serum leptin concentrations were higher in male ZnD rats than in controls. Phosphorylation of muscle Akt protein, an insulin receptor (IR) signaling intermediate, was lower in female ZnD rats than in controls at wk 15, but they did not differ in phosphorylation of IR. Maternal Zn deficiency resulted in greater serum IGF-1 concentrations and the excessive postnatal weight gain in their offspring as well as impaired subsequent glucose sensitivity. It was associated with gender-specific alterations in the serum leptin concentration and the insulin signaling pathway. These findings suggest that suboptimal maternal Zn status induces long-term changes in the offspring related to abnormal glucose tolerance.
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Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Efectos Tardíos de la Exposición Prenatal , Zinc/deficiencia , Animales , Glucemia , Peso Corporal/efectos de los fármacos , Femenino , Hígado/anatomía & histología , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Músculo Esquelético/metabolismo , Tamaño de los Órganos , Embarazo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Zinc/sangre , Zinc/metabolismoRESUMEN
OBJECTIVES: Zinc (Zn) homeostasis in adults is achieved principally through a balance between intestinal absorption and excretion involving adaptive mechanisms programmed by levels of dietary Zn. Zn absorption in infants is not as tightly regulated as that in adults, which may induce potential toxicity in infants due to the relatively high capacity of Zn absorption. We hypothesized that intestinal Zn homeostasis is developmentally regulated and depends on intestinal maturation, which in turn affects Zn transporter regulation. MATERIALS AND METHODS: Cultured human fetal (FHs 74 Int, F) and adult (Caco-2: undifferentiated, U; differentiated, D) intestinal cells were used to determine developmental differences in Zn uptake and effects of Zn exposure on Zn transporters. RESULTS: Zn uptake rates in F and U cells were higher compared with D cells (F, 9-fold; U, 3-fold). F cells were more intolerant to Zn exposure than were U or D cells (LD50 = 67.9 +/- 5.3; 117.0 +/- 5.2; 224.4 +/- 3.7 micromol/L, respectively). Two mechanisms were involved in developmental regulation of Zn homeostasis: differential Zn transporter expression and differential response to Zn exposure. In F cells, zinc-regulated transporter (ZRT)/iron-regulated transporter (IRT)-like protein (Zip)4 expression was undetectable; Zn (50 micromol/L) increased levels of Zn transporter (ZnT)1, ZnT2, and metallothionein-1 mRNA and ZnT1 protein. U and D cells had higher mRNA expression of ZnT1 (U: 5-fold; D: 7-fold, respectively) and ZnT2 (U: 2-fold; D: 9-fold, respectively) than F cells, and D cells also had higher Zip4 expression (3-fold) than U cells. In U cells, Zn exposure increased Zip4 protein level, but not membrane-associated abundance. However, in D cells, Zn exposure decreased both the Zip4 protein level and membrane-associated abundance. CONCLUSIONS: Zn absorption is developmentally regulated through intestinal Zn efflux and sequestration and import mechanisms, which may be responsible for differences in Zn absorption observed between infants and adults.
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Proteínas de Transporte de Catión/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Zinc/metabolismo , Adulto , Transporte Biológico/genética , Células CACO-2 , Proteínas de Transporte de Catión/genética , Diferenciación Celular , Células Cultivadas , Expresión Génica , Homeostasis , Humanos , Absorción Intestinal , Metalotioneína/genética , Metalotioneína/metabolismo , ARN Mensajero/metabolismo , Zinc/farmacocinéticaRESUMEN
Intestinal zinc (Zn) absorption and liver Zn mobilization are presumed to regulate Zn homeostasis. Several Zn transporters have been identified; however, their contribution to Zn homeostasis is poorly understood. Moreover, their regulation during periods of growth is unknown. To characterize the mechanisms that maintain Zn status, weanling rats were fed control (25 mg/kg), marginally low (MLZ; 15 mg/kg), low (LZ; 7 mg/kg), or very low (VLZ; <1 mg/kg) Zn diets for 3 wk and effects on jejunum Zip4 and ZnT1 and hepatic Zip1 and ZnT1 were assessed. Another control group was pair-fed (PF) to VLZ. The MLZ rats had lower jejunum ZnT1 protein abundance than the control. In the LZ group, we detected increased jejunum Zip4 mRNA expression and hepatic ZnT1 protein abundance and reduced jejunum Zip4 and ZnT1 and hepatic Zip1 protein abundance. VLZ had lower jejunum ZnT1 mRNA and protein abundance and hepatic Zip1 and ZnT1 protein abundance compared with the PF group. Zip4 protein was present at the intestinal villus tip in controls but was detected on the apical membrane throughout the entire villus in LZ rats. ZnT5 protein in jejunum was always detected at the apical membrane and also at the basolateral membrane of VLZ rats. In contrast, ZnT7 was found intracellularly in jejunum. Our data suggest that effects of Zn deficiency on Zn homeostasis occurs biphasically during marginal Zn deficiency through increased intestinal Zn uptake capacity and reduced intestinal Zn efflux, then during more pronounced degrees of Zn deficiency through decreased liver Zn accretion and increased hepatic Zn efflux back into circulation. These results assist in our understanding of how mammals regulate Zn homeostasis.