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Uteroplacental Restriction And Subsequent Impaired Mammary Function Programs Catch-Up Growth, Hyperglycemia, Impaired Glucose Tolerance And Obesity
Wlodek, ME; O'Dowd, R; Mibus, AL; Leone, FM; Wyss, O; Westcott, KT; Robinson, JS; Owens, JA
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Journal of the Society for Gynecologic Investigation
Objectives: Catch-up growth in infancy and childhood following fetal growth restriction is implicated as contributing to increased risks of hypertension, insulin resistance and obesity in the adult. In Western society, impaired uteroplacental blood flow and subsequent reduced oxygen and nutrient delivery across the placenta is characteristic of human intrauterine growth restriction. We have shown that uteroplacental restriction in the rat impairs mammary function, pup milk intake and perinatal growth and therefore determined its effects on postnatal growth, glucose homeostasis and body composition. Methods: Bilateral uterine vessel ligation (Restriction) or sham surgery (Control) was performed on day 18 of gestation in Wistar Kyoto rats. Litter size in a second group of Sham rats was randomly reduced at birth to that of Restricted (Reduced Litter Control). Pup weight was measured from 3 days to 22 weeks. At 6 months, fasted and challenged (10 minutes following intravascular glucose, 0.5 g/kg) plasma glucose and free fatty acid (FFA) concentrations were measured via chronic indwelling vascular catheter and body composition determined. Data were analysed by ANOVA. Results: In females, Restricted had increased fractional growth rate during lactation and after weaning and were similar in weight at 6 months compared to Reduced Litter Control (p and lt;0.05), but both were lighter than Controls (p and lt;0.05). In males, Restricted had increased fractional growth rate after weaning, but were lighter at 6 months compared to Reduced Litter Control (p and lt;0.05). Restricted adult males and females had increased fasting plasma glucose compared to Reduced Litter Control and Sham Controls (p and lt;0.05), while Restricted males also had higher plasma glucose after glucose challenge, compared to Controls (p and lt;0.05). Restricted females but not males exhibited increased abdominal circumference and adiposity compared to both Controls (p and lt;0.05) and plasma FFA were not different. Conclusions: Uteroplacental restriction reduces size at birth, induces postnatal catch-up growth and fasting hyperglycaemia in the aged rat as well as glucose intolerance in males. Adult females exhibited increased adiposity following restriction, suggesting sex differences in programming of obesity and that glucose homeostasis is impaired via pathways at least partly independent of body composition. There may be important adult-onset disease and growth consequences of nutrition provided to the growth restricted infant during lactation and weaning.
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