Neonatal Catch Up Growth Increases Diabetes Susceptibility But Improves Behavioral and Cardiovascular Outcomes of Low Birth Weight Male Mice

Abstract

Premature infants are at increased risk for persistent growth failure, neurodevelopmental impairment, hypertension, and diabetes. Rapid neonatal growth has been linked to the increasing prevalence of diabetes and obesity. Nutritional goals for the premature infant with incipient growth failure have thus become a source of controversy. We used isogenic mice with natural variation in perinatal growth to test the hypothesis that neonatal catch up growth improves the neurobehavioral and cardiovascular outcomes of lowbirth weight mice, despite an increase in diabetes susceptibility. Adult mice that experienced prenatal and neonatal growth restriction had persistent growth failure, hypertension, and neurobehavioral alterations. When switched from standard rodent chow to a hypercaloric diet, growth restricted mice were protected from diet-induced obesity. Among low-birth weight male mice, neonatal catch up growth normalized neurobehavioral and cardiovascular phenotypes, but led to insulin resistance and high fat diet-induced diabetes. Among low-birth weight female mice, neonatal catch up growth did not prevent the development of adult hypertension and significantly increased measures of anxiety, including self-injury and the avoidance of open spaces. These studies support the importance of the perinatal environment in the resetting of adult disease susceptibility and suggest an earlier window of vulnerability among growth restricted female mice. (Pediatr Res 66: 53-58, 2009) R estricted perinatal growth is an independent risk factor for the development of type 2 diabetes, hypertension, and coronary heart disease (1,2). The primary animal models of programmed adult disease induce fetal growth restriction through maternal nutrient restriction or uterine artery ligation (3). The development of diabetes and obesity in these models has been most dramatic when rodent pups are cross-fostered to well-nourished dams and then weaned to postnatal high-fat diets (4,5). These studies are consistent with epidemiologic data linking excessive weight gain in infancy with adult metabolic syndrome (6). Although these data suggest that restriction of neonatal nutrition might improve adult metabolic health, a comprehensive approach is essential when considering the long-term consequences of perinatal dietary alterations (7).Preterm delivery increases the risk of impaired growth during a critical window of brain development. By 36-wk postmenstrual age, ϳ90% of premature infants have growth failure (weight less than the 10th percentile of reference fetuses) (8). This perinatal growth failure is associated with permanent reductions in adult weight and height (9). It follows that premature delivery greatly increases the risk of neurodevelopmental impairment, insulin resistance, and adult hypertension (10 -12). As parallel epidemics of prematurity and obesity unfold, there is a critical need for research-based neonatal nutritional recommendations that seek to optimize short-term health and long-term outcomes.We previously evaluated th...

Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice

“…This has been observed in rat and mouse models with bilateral uterine artery ligation or isocalorie low protein nutrition during pregnancy (Simmons et al 2001, Song et al 2008, Cripps et al 2009, Hermann et al 2009). In addition, these data are also supported by human observations (Baker et al 1989, Levy-Marchal & Czernichow 2006.…”

IUGR with infantile overnutrition programs an insulin-resistant phenotype through DNA methylation of peroxisome proliferator–activated receptor-γ coactivator-1α in rats

“…Numerous studies have concluded that IUGR individuals, especially those with postnatal accelerated growth, are prone to develop insulin resistance and T2DM in adulthood (11)(12)(13). Using a well-established rodent model, these experiments have found that CG-IUGR rats had higher methylation level of specific CpG sites of PGC-1α promoter, in contrast, reduced PGC-1α transcription activity, mitochondrial content as well as protein level of key components of insulin-signaling pathway in liver and muscle tissues.…”

“…Many intrauterine growth restriction (IUGR) infants experience postnatal accelerated growth (8), begetting shortterm (9) and long-term health benefits, especially in cognition and academic achievement (10). However, emerging evidence suggests that IUGR followed by postnatal accelerated growth (CG-IUGR) plays a role in the programing of adult metabolic disease risk (11)(12)(13), and the underlying molecular pathogenesis is unclear. Nevertheless, the epigenetic dysregulation has been implicated.…”

Neonatal Macrosomia Is an Independent Risk Factor for Adult Metabolic Syndrome

“…Insulin levels were measured on plasma collected from fasting mice immediately prior to glucose tolerance testing, as previously described [12] . Following the endocrine tests, tail cuff systolic blood pressure (SBP) and heart rate were recorded for 5 consecutive days, as previously described [11,12] . During the final week on the baseline diet, feed intake was recorded and an exercise wheel (35 cm circumference, Thoren Caging Systems, Hazleton, Pa., USA) was placed inside each cage to evaluate voluntary activity.…”

“…While beginning our investigation into the long-term consequences of natural perinatal growth variation, we demonstrated that spontaneous neonatal growth restriction programs the development of metabolic syndrome in isogenic mice [11,12] . As in other programming models, marked sexual dimorphism was noted, with neonatal growth restriction eliciting hypertension in adult male mice and glucose intolerance in adult female mice [12] .…”