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Research Project: Developmental Determinants of Obesity in Infants and Children

Location: Children's Nutrition Research Center

Title: Fetal growth restriction promotes physical inactivity and obesity in female mice

Author
item BAKER, MARIA - Children'S Nutrition Research Center (CNRC)
item LI, GEE - Children'S Nutrition Research Center (CNRC)
item KOHORTS, JOHN - Children'S Nutrition Research Center (CNRC)
item WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)

Submitted to: International Journal of Obesity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/20/2013
Publication Date: 9/10/2013
Citation: Baker, M.S., Li, G., Kohorts, J.J., Waterland, R.A. 2013. Fetal growth restriction promotes physical inactivity and obesity in female mice. International Journal of Obesity. 146:1-7.

Interpretive Summary: We showed several years ago that in the 'agouti' (Avy/a) mouse model, offspring of obese Avy/a mothers grew up to be more obese themselves, suggesting 'transgenerational amplification of obesity'. We investigated this model in more detail, and made several important discoveries. First, we determined that the obesity-promoting effect of being born to an Avy/a mother occurs during fetal development (not during the suckling period). Paradoxically, we found that offspring of obese Avy/a mothers are growth restricted in utero (unlike offspring of obese women, who tend to have elevated birth weight). Importantly, this fetal growth restriction led to adult obesity only in female offspring, and this appeared to be caused by a persistent blunting of spontaneous physical activity. If a similar effect occurs in humans, this would suggest that parents of low-birth weight infants should make extra efforts to encourage physical activity in their children.

Technical Abstract: Environmental exposures during critical periods of prenatal and early postnatal life affect the development of mammalian body weight regulatory mechanisms, influencing lifelong risk of obesity. The specific biological processes that mediate the persistence of such effects, however, remain poorly understood. The objectives of this study were to determine the developmental timing and physiological basis of the obesity-promoting effect previously reported in offspring of obese agouti viable yellow (Avy/a) mothers. Newborn offspring of obese Avy/a and lean (a/a) mothers were cross-fostered shortly after birth to study separately the effects of in utero or suckling period exposure to Avy/a dams. Body composition, food intake, physical activity and energy expenditure were measured in offspring shortly after weaning and in adulthood. We found that offspring of obese Avy/a dams paradoxically experienced fetal growth restriction, which was followed by adult-onset obesity specifically in females. Our main analyses focused on wild-type (a/a) offspring, because a subset of adult Avy/a offspring contracted a kidney disease resembling diabetic nephropathy. Detailed physiological characterization demonstrated that, both shortly after weaning and in adulthood, female wild-type mice born to Avy/a mothers are not hyperphagic but have reduced physical activity and energy expenditure. No such coordinated changes were detected in male offspring. Mediational regression analysis of our longitudinal data supported a causal pathway in which fetal growth restriction persistently reduces physical activity, leading to adult obesity. Our data are consistent with several recent human epidemiological studies showing female-specific effects of perinatal nutritional restriction on later obesity, and provide the novel mechanistic insight that this may occur via permanent and sex-specific changes in one's inherent propensity for physical activity.