Reductions in caloric intake and early postnatal growth prevent glucose intolerance and obesity associated with low birthweight
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- Jimenez-Chillaron, J.C., Hernandez-Valencia, M., Lightner, A. et al. Diabetologia (2006) 49: 1974. doi:10.1007/s00125-006-0311-7
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Low birthweight (LBW) and rapid postnatal weight gain, or catch-up growth, are independent risk factors for the development of obesity and diabetes during adult life. Individuals who are both small at birth and have postnatal catch-up growth are at the highest risk. We hypothesised that dietary interventions designed to attenuate catch-up growth in LBW subjects may have long-term beneficial consequences.
Materials and methods
We used our previously described mouse model of LBW-associated diabetes, created by restricting maternal food intake to 50% during the last week of gestation. Control (C) dams and dams that had been subjected to undernutrition (U) were then provided either chow ad libitum after delivery or 50% food restriction on a per-day basis from delivery until weaning. We designated the resulting four groups control-control (CC), undernutrition-control (UC), control-undernutriton (CU) and undernutrition-undernutrition (UU), indicating the prenatal and postnatal experimental conditions, respectively. Carbohydrate metabolism and adiposity were assessed prospectively in offspring until age 6 months.
Males that were small at birth and exhibited early postnatal catch-up growth developed glucose intolerance and obesity by age 6 months. In contrast, LBW mice without catch-up growth (UU) remained smaller than controls (CC), and glucose intolerance and obesity was prevented. Similarly, mice with normal birthweight that had blunted catch-up growth (CU) were leaner and had better tolerance test than CC mice. Catch-up growth during the first week of life correlated better than birthweight with glucose, fat mass and glucose tolerance up to 6 months of age.
Prevention of early catch-up growth reversed the development of glucose intolerance and obesity in our mouse model of LBW-associated diabetes.
KeywordsCaloric restrictionCatch-up growthDiabetesGrowth rateIntrauterine growth retardationLow birthweightObesity
appropriate for gestational age
dual-energy X-ray absorptiometry
intrauterine growth retardation
small for gestational age
Many epidemiological and animal studies have linked a suboptimal nutritional environment during pregnancy and low birthweight (LBW) with increased susceptibility to chronic disease during adult life [1–3]. The developmental programming hypothesis proposes that insults or stimuli acting during critical windows of development, including fetal and/or early postnatal periods, can produce permanent alterations in cell/tissue structure and function .
A growing body of evidence suggests that rapid postnatal weight gain, or catch-up growth, is also associated with increased susceptibility to obesity and type 2 diabetes [5, 6]. The risk associated with catch-up growth is even higher when catch-up growth operates during periods characterised by rapid increments in weight and length/height, such as early postnatal life [6–8]. Such patterns of accelerated postnatal growth are common in individuals who are small for gestational age (SGA) and may be considered a physiological adaptation that allows them to reach their genetically programmed weight and/or height after a period of growth retardation [9, 10]. Not surprisingly, individuals who are both small at birth and have postnatal catch-up growth are at high risk of (central) obesity, glucose intolerance and diabetes [8, 9, 11–14].
Thus, rapid postnatal growth in either SGA children or children who are appropriate for gestational age (AGA) may contribute significantly to the development of metabolic syndrome during adult life. Here, we postulate that dietary interventions designed to limit catch-up growth in LBW infants or to reduce early postnatal growth rates in AGA infants may have beneficial long-term consequences. To test this hypothesis, we used our mouse model of LBW-associated diabetes . In this model, maternal nutrient restriction during the final week of gestation reduces birthweight in offspring. Normalisation of maternal nutrition at delivery is associated with catch-up growth in offspring, such that offspring weight normalises by the age of 3 weeks. Since nutrient availability is a key determinant of postnatal growth, we restricted maternal food availability during the 3 weeks of lactation in order to prevent early postnatal catch-up growth in LBW mice. In this context, we evaluated the relative contributions of intrauterine growth retardation (IUGR) and catch-up growth to the development of adult metabolic phenotypes, including body weight, fat mass and glucose homeostasis. Moreover, we defined the potential critical period(s) of growth that can influence these adult metabolic phenotypes.
Materials and methods
Animal care and experimental protocol
Dual-energy X-ray absorptiometry scanning
Body composition was analysed using dual-energy X-ray absorptiometry (DEXA) (Hologic, Waltham, MA, USA), as described .
Insulin and leptin were measured in 5 μl serum samples by ELISA (Crystal Chem, Downers Grove, IL, USA). Whole-blood glucose was measured with a Glucometer Elite (Bayer, Elkhart, IN, USA). Total adiponectin was measured by ELISA in 5 μl aliquots of serum diluted at 1:100 (Linco Research, St Charles, MO, USA).
Results are expressed as mean±SEM. For group comparisons, statistical analysis was performed using a two-tailed t-test or ANOVA (Statview, Cary, NC, USA); p values ≤0.05 were considered significant.
Growth effects of early postnatal reductions in caloric intake
As previously reported , 50% global caloric restriction during the last week of gestation produced a 25% decrease in body weight at birth (UC vs CC mice, p<0.001) (Fig. 1b). Length of pregnancy was similar in all groups (data not shown), and pup number was slightly, although not significantly, reduced in the pregnancies with maternal undernutrition (CC, 10±1.0 mice/litter; CU, 11±1.6; UC, 8.5±0.5; UU, 8.2±0.9). Litters were normalised to eight pups in all groups. As previously demonstrated, UC mice exhibited catch-up growth, with weights similar to CC offspring by the third week of life (Fig. 1c). In contrast, offspring in postnatal food restriction groups (CU, UU) showed a 50% reduction in body weight at the time of weaning compared with CC (Fig. 1c). Interestingly, UU mice, which were smaller at birth (25% decrease relative to CC), also showed catch-up growth (relative to CU mice), reaching the same body weight as CU mice by 3 weeks of life. While CC and UC mice were similar in weight up to age 6 months, weights of CU and UU mice remained significantly lower than those of CC mice despite ad libitum feeding after weaning (Fig. 1d).
Food intake at 2 and 6 months of age
Body weight, fat mass and fat-free mass of 6- and 12-month-old male mice
Body weight (g)
Fat mass (g)
Relative body fat (%)
Abdominal fat (%)
Fat-free mass (g)
Relative fat-free mass (%)
We also assessed fat-free mass (FFM) in offspring mice (Table 2). Total FFM was similar between CC and UC mice, whereas it was significantly reduced in CU and UU mice at 6 months and in UU mice at 12 months. Since CU and UU mice have reduced body weight, we also assessed relative FFM; relative FFM was preserved in CU and UU mice. Thus, the overall ratio of fat mass to FFM (28 vs 72%) was increased in UC mice but remained normal in UU mice (20 vs 80%).
We next assessed serum markers of adipocyte mass and function. Serum leptin levels paralleled fat mass in all groups (r=0.67, p=0.001), with a trend to higher levels in LBW mice with catch-up growth (UC) (Fig. 4c). Levels of adiponectin, another fat-derived adipokine, tended to be lower in UC offspring than in CU or UU mice by 6 months of age (Fig. 4d).
Correlations of birthweight (BW) and growth rate (GR) with adult phenotypes at 6 months
GR (1–6 weeks)
GR (1st week)
GR (4th week)
GR (1–3 weeks)
GR (4–6 weeks)
Total body fat
GTT AUC at 6 months
We next wished to determine which time period(s) within the first 6 weeks of life accounted for the correlations between early postnatal growth and adult metabolic phenotypes. We focused on growth rates during the first 3 weeks (GR 1–3) and the fourth to sixth (GR 4–6) weeks of life, since these are the two periods that coincided with growth spurts and during which differences between groups were most marked. GR 1–3 strongly correlated with body weight, fat mass (whole-body and abdominal), insulin and glucose AUC (Table 3). GR 4–6 correlated only with body weight and abdominal fat. Within the first 3 weeks of life, the growth rate during week 1 was most strongly linked to metabolic phenotypes. Indeed, the regression coefficients were similar in magnitude and direction to those for GR 1–6, suggesting that growth rate during the first week of life is a major contributor to the final adult phenotype. Growth rates during week 4 of life, in contrast, were inversely correlated with body weight. Taken together, these data suggest that catch-up growth during the first week of life is a dominant factor in the development of adult metabolic disturbances in our mouse model of LBW.
Our data demonstrate that prevention of early catch-up growth prevents the development of glucose intolerance and obesity in our mouse model of LBW-associated diabetes. Two important implications arise from this finding: (1) rapid early postnatal growth is more detrimental than LBW per se for the development of adult metabolic phenotypes, at least in our experimental model; and (2) in agreement with the developmental programming hypothesis , both fetal and early postnatal periods are critical windows during which perturbations in nutritional status can have long-term consequences. Furthermore, these data suggest that prenatal metabolic adaptations are not completely fixed and may be reversed by subsequent postnatal interventions.
Several recent studies have begun to address the effects of postnatal nutritional and hormonal interventions on later disease risk in rodents. For example, female offspring of rats maintained on a low-protein diet (8%) throughout pregnancy and lactation were protected from later obesity but developed hypertension compared with controls . In addition, normal-weight mice that were nursed by dams fed a low-protein diet showed slow postnatal growth rate, reduced body weight and increased longevity compared with controls [19, 20]. Moreover, postnatal dietary supplementation with ω-3 fatty acids can prevent hyperleptinaemia and hypertension in offspring of mothers treated with dexamethasone during pregnancy . Conversely, postnatal overfeeding in rats to accelerate postnatal growth reproduces some aspects of the human phenotype, including increased risk of later development of obesity, hyperinsulinaemia, hypercholesterolaemia and diabetes . Finally, two recent studies have indicated a role for alterations in the early neonatal secretion and/or action of leptin, a key hormonal sensor and effector of nutrient adequacy, in modulating LBW-associated metabolic phenotypes. Neonatal leptin surges occurred earlier in U offspring than in controls , while pharmacological doses of leptin administered to LBW rat pups during the nursing period prevented obesity and hyperleptinaemia with high-fat feeding . While discordant in some aspects, these papers suggest an important role for the timing and magnitude of neonatal leptin in influencing the risk of obesity in later life . Together with our data, these studies indicate that manipulation of postnatal nutrition and hormonal responses can prevent developmental programming. Nevertheless, it remains unclear whether the nutritional and hormonal interventions that have been described have an impact on early growth rate, and whether the reported effects on adult phenotypes are mediated through the modulation of postnatal catch-up growth.
In our experiment, modulation of postnatal catch-up growth was achieved through relative calorie restriction during the suckling period. Similar findings have been reported in humans, where preterm LBW babies that were fed a low-nutrient diet during the first 2 weeks of life had reduced postnatal growth rates but lower markers of insulin resistance and improved endothelial function by age 13 to 16 years [14, 26]. These authors concluded that relative undernutrition early in life (2 weeks after birth) may have long-term beneficial effects. Conversely, overnutrition of AGA children in terms of either high-protein  or rich milk formulas  has been linked to increased C-peptide levels and high blood pressure, respectively. Animal and human data, considered together, suggest that postnatal nutritional interventions can have potent effects on the later risk of chronic disease.
Still, we recognise that postnatal undernutrition may not be a viable strategy to modulate growth rate in SGA and/or AGA children because of concerns that inadequate nutrition during early postnatal life could have adverse effects on central nervous system development, cognitive function and the risk of infection [29–31]. An important challenge will be to find strategies that balance adequate nutritional status and postnatal growth while preventing excess catch-up growth. Future investigation will be focused on components and/or markers of the metabolic and hormonal milieu that may mediate postnatal catch-up growth, including maternal milk composition as influenced by diet.
An important question that we hoped to elucidate concerns the developmental window(s) during which (accelerated) postnatal weight gain has a critical effect on adult health. To this end, we profiled the specific growth rate in our mouse cohorts from birth to 6 month of age. As described, growth rate was highest during the first 6 (GR 1–6) weeks of life, remaining at very low and constant levels beyond this age. Growth rate during this early stage of life was characterised by two growth spurts occurring during the first and fourth weeks of life, periods that could be considered equivalent to infancy and adolescence in humans . Here we show that growth rate during the first week of life (GR 1) has the strongest positive correlation with body weight, fat mass, insulin and glucose tolerance by 6 months of age, implying that the faster the growth during this period, the higher the risk of obesity and glucose intolerance. This suggests that the first week of life appears to be the most critical period of development that can influence adult health in the mouse. Furthermore, these data imply that modulation of growth during this time frame may have long-term consequences for health outcomes. Additional experiments, with daily assessment of growth rates, will be required to narrow the critical period(s) that contribute to increased risk of disease in our mouse cohorts. This will allow us to develop postnatal interventions intended to restrict growth rate only during this period(s) of maximal susceptibility to developmental programming.
In humans, there is some conflict regarding the critical period(s) of growth that influence(s) adult phenotype. Nevertheless, the general consensus is that, in agreement with our data, early infancy is the most critical window, since catch-up postnatal growth is largely seen within the first 2 years . Some authors report that the two first weeks of life [14, 26, 33] can have long-term consequences, while others suggest windows within 1–3 years [5, 34–36] or 4–11 years [37–39]. The variability of these conclusions may be related to study design, since in some cases data from early stages of life (first weeks or months) were not recorded, with the first postnatal data collection only several years after birth. This makes it difficult to profile accurately the very early stages of life and analyse their impact on adult outcomes. More work needs to be done to profile early periods of life in humans and to determine their potential influence on health outcomes.
Increased adiposity is a serious complication of LBW and subsequent catch-up growth in rodents and humans . While our initial cohort of U mice did not have significantly increased fat mass, as determined by carcass analysis , we detected significantly increased fat in both whole-body and abdominal compartments by DEXA analysis in two independent cohorts. Although we cannot completely address the reason(s) that could account for this difference, we speculate that subtle differences in fat mass were not detected by the original methods. Development of obesity in UC mice suggests that catch-up growth actually reflects fat mass accretion (i.e. catch-up fat). Conversely, fat mass is reduced in UU mice that are unable to catch up in weight to matched controls. It is also important to note that relative FFM, which plays a central (positive) role in glucose homeostasis, is preserved in UU and CU mice but slightly reduced in UC mice. Thus, dysregulated glucose homeostasis in UC mice may be related not only to increased fat accretion, but also to an overall shift in body composition (as reflected by the increased fat/FFM ratio).
What are the mechanisms underlying increased adiposity in relationship to catch-up growth? In rats, catch-up growth after a period of semi-starvation is characterised by accelerated and preferential recovery of fat mass compared with lean mass [9, 40], an effect potentially mediated by suppressed muscle thermogenesis, resulting in a shift of nutrients (glucose) to adipose tissue . To find out whether a similar mechanism accounts for the increased fat accretion in UC mice during early stages of growth will require additional studies. Several other mechanisms may contribute to increased adiposity in relationship to catch-up growth. For example, increased food intake may contribute to increased adiposity in UC mice. While we do not have any measurement of food intake during the suckling period, when catch-up growth occurs food intake is similar in UC mice compared with CC mice at both 2 and 6 months of age. While these data indicate that postweaning food intake does not account for increased adiposity in UC mice, additional experiments will be required to evaluate potential differences in energy intake during the suckling period. We speculate that dysregulation of nutrient-stimulated insulin secretion, favouring inappropriate degrees of hyperinsulinaemia, may also contribute to fat accretion in our model. Other hormones and growth factors may also alter body composition in the setting of catch-up growth, including insulin-like growth factors, glucocorticoids or leptin [41, 42], or altered expression of genes regulating fat tissue development and/or differentiation . Finally, altered timing and patterns of critical hormonal responses, including leptin, may contribute to the disruption of central nervous system architecture and function. This may lead, in turn, to programmed changes in leptin sensitivity and the balance of other pathways regulating satiety and energy expenditure—an important area for future investigation [23, 25].
In conclusion, our data demonstrate that rapid postnatal growth, independent of birthweight, is a major contributor to later risk of adult disease. Preventing postnatal catch-up growth by modulating nutrient availability in LBW mice completely reverses the programming of obesity and glucose intolerance. In addition, deceleration of early growth rate in normal weight mice also improves glucose tolerance by age 6 months. These data suggest that reducing early postnatal growth rate in both SGA and AGA children could have potential beneficial consequences for long-term health. Thus, our data provide support for the idea that carefully controlled alterations in calorie intake and/or composition, designed to attenuate catch-up growth and accretion of adipose tissue, may be clinically beneficial in LBW individuals, in order to minimise the risk of adult disease. Future investigations will be critical in identifying mechanisms and markers of postnatal catch-up fat accretion, and in designing optimal nutritional interventions in key therapeutic windows, in order to prevent overnutrition in high-risk infants.
We gratefully acknowledge grant support to M. E. Patti from NIDDK (DK 062948), the American Diabetes Association and the Adler Foundation, and the resources from the Joslin Diabetes and Education Research Center (P30 DK36836).