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1 Obstetrics and Gynecology, David-Geffen School of Medicine at University of California Los Angeles, Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance, CA, USA
* To whom correspondence should be addressed. E-mail: mdesai{at}obgyn.humc.edu.
Maternal undernutrition in pregnancy is associated with intrauterine growth restriction (IUGR). With enhanced nutrient support, IUGR newborns may demonstrate a rapid catch-up growth and, paradoxically, the development of obesity in adult offspring. As hypothalamic control of appetite is likely set during the fetal or neonatal period, nutrient stress and perhaps nutrient enhancement during these periods may alter appetite setpoints and contribute to programming of adult obesity. We postulated that the degree of nutrient enhancement during the newborn period may modulate the programming of appetite regulating hormones, body composition and the propensity to adult obesity in IUGR newborns. Pregnant rats received from day 10 to term gestation and throughout 21 days of lactation either ad libitum (AdLib) food (control, N=12) or 50% food-restriction (FR, N=12) to produce IUGR newborns. The two groups of offspring were studied at day 1 (AdLib vs FR), and to create two distinct model groups of newborn catch-up growth (immediate, delayed) among the IUGR newborns, half of the IUGR pups born to FR mothers were cross-fostered to AdLib dams whereas the other half were nursed by their own FR dams. Similarly, half of the pups born to AdLib mothers were nursed by AdLib dams, and half cross fostered to FR dams. Thus there were 4 groups of pups at 3 weeks: the IUGR immediate catch-up growth (FR/AdLib); IUGR delayed catch-up growth (FR/FR); Control (AdLib/AdLib), and a lactation FR control group (AdLib/FR). From 3 weeks to 9 months of age, all offspring were provided ad libitum rat chow. Daily body weights and food intake from weaning to 9 months was recorded. Body composition was determined by DEXA at 3 weeks and 9 months. Plasma leptin and ghrelin levels were analyzed at ages 1 day, 3 week and 9 month. Maternal FR during pregnancy resulted in IUGR pups (6.0 ± 0.3 vs 7.1 ± 0.3 g, p<0.01) with decreased leptin (0.66 ± 0.03 vs 1.63 ± 0.12 ng/ml, p<0.001) and increased ghrelin levels (0.43 ± 0.03 vs 0.26 ± 0.02 ng/ml, p<0.01). Maternal FR during lactation (FR/FR) further impaired the IUGR offspring growth at 3 weeks. However, by 9 months of age these pups had attained normal body weight, % body fat and plasma leptin levels. Conversely, IUGR offspring nursed by AdLib dams (FR/AdLib) exhibited rapid catch-up growth at 3 weeks, and continued accelerated growth resulting in increased weight, % body fat, and plasma leptin levels. These results suggest that the degree of newborn nutrient enhancement and timing of IUGR newborn catch-up growth, may determine the programming of orexigenic hormones and offspring obesity.
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