Content area
Full Text
OBJECTIVE-We have examined maternal mechanisms for adult-onset glucose intolerance, increased adiposity, and atherosclerosis using two mouse models for intrauterine growth restriction (IUGR): maternal protein restriction and hypercholesterolemia
RESEARCH DESIGN AND METHODS-For these studies, we measured the amino acid levels in dams from two mouse models for IUGR: 1) feeding C57BL/6J dams a protein-restricted diet and 2) feeding C57BL/6J LDL receptor-null (LDLR^sup -/-^) dams a highfat (Western) diet.
RESULTS-Both protein-restricted and hypercholesterolemic dams exhibited significantly decreased concentrations of the essential amino acid phenylalanine and the essential branched chain amino acids leucine, isoleucine, and valine. The proteinrestricted diet for pregnant dams resulted in litters with significant IUGR. Protein-restricted male offspring exhibited catch-up growth by 8 weeks of age and developed increased adiposity and glucose intolerance by 32 weeks of age. LDLR^sup -/-^ pregnant dams on a Western diet also had litters with significant IUGR. Male and female LDLR^sup -/-^ Western-diet offspring developed significantly larger atherosclerotic lesions by 90 days compared with chowdiet offspring.
CONCLUSIONS-In two mouse models of IUGR, we found reduced concentrations of essential amino acids in the experimental dams. This indicated that shared mechanisms may underlie the phenotypic effects of maternal hypercholesterolemia and maternal protein restriction on the offspring. Diabetes 58:559-566, 2009
In humans, malnutrition during pregnancy results in babies with lower birth weight and an increased risk of neonatal mortality and morbidity (1). Low birth weight is also associated with an increased risk for certain chronic diseases, including type 2 diabetes, cardio- vascular disease, and hypertension (2-4). One proposed explanation linking low birth weight to chronic diseases is the Barker "thrifty phenotype" hypothesis, which postulates that the lack of adequate nutrients in the intrauterine environment "programs" the offspring for survival in a nutrient-poor world. It follows that if the actual postnatal environment is not nutrient poor but instead nutrient rich, metabolic pathways will have been "malprogrammed," leading to adult-onset metabolic syndrome diseases, including atherosclerosis and diabetes (5). A great deal of evidence now supports the Barker hypothesis (6); therefore, current research in humans and in animal models is focused on specific mechanisms for in utero programming (4).
Many types of maternal stresses in different animal models have been used to produce intrauterine growth restriction (IUGR) (7). In the current study, we used two...