Fetal growth restriction promotes physical inactivity and obesity in female mice

Abstract

Background: 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.

Objective: 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 (A(vy)/a) mothers.

Design: Newborn offspring of obese A(vy)/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 A(vy)/a dams. Body composition, food intake, physical activity and energy expenditure were measured in offspring shortly after weaning and in adulthood.

Results: Offspring of obese A(vy)/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 A(vy)/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 A(vy)/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.

Conclusions: 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.

Figure 1

Fetal growth restriction promotes obesity specifically in female offspring. Body weight vs. age of male (a) and female (b) a/a offspring cross fostered among lean a/a and obese A^vy/a dams. Each plot represents mean ± SEM of 20–37 LL offspring from 14–15 litters, 24–50 LO offspring from 28–32 litters, 19–25 OL offspring from 11–12 litters, and 4–9 OO offspring from 3–5 litters. (Detailed sample size tabulation in Table S1a–b.) Asterisks in main plots indicate significance of OL vs. LL differences only. (P values for all group comparisons in Table S1c.) Insets are box plots of body weight at P21, each indicating median, 25^th–75^th percentiles, and 5^th–95^th percentiles. (c) and (d) are box plots illustrating group differences in body composition (% fat) of P140 a/a male and female offspring, respectively. Number of mice studied is indicated above each box. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 relative to LL mice of same age and sex.

Figure 2

Independent experiment confirms that fetal growth restriction promotes increased adult body weight and adiposity only in female offspring. Body weight vs. age of a/a male (a) and female (b) LL and OL offspring. Each plot represents mean ± SEM of 21–36 LL offspring from 12–18 litters, and 13–34 OL offspring from 11–17 litters. (Detailed sample size tabulation in Table S2a–b.) Insets are box plots of % body fat at P140, each indicating median, 25^th–75^th percentiles, and 5^th–95^th percentiles. Number of mice studied is indicated above each box. *P<0.05 relative to LL mice of same age and sex.

Figure 3

Fetal growth restriction reduces physical activity and energy expenditure in a/a females but not males. (a) Dietary intake, (b) energy expenditure, and (c) total physical activity of a/a LL and OL mice, by sex and age. (Dietary intake and energy expenditure data have been least-squares normalized for lean mass and fat mass.) For each mouse, three days of metabolic cage data were collapsed into 24 1-hour averages. Each plot represents mean ± SEM of 12–13 LL offspring from 7 litters, and 12 OL offspring from 8 litters. Statistical analyses were performed separately by light and dark periods (indicated by shading). *P<0.05, ***P<0.001, ****P<0.0001 relative to LL mice of same age and sex.

Figure 4

Physical activity levels ‘track’ into adulthood and predict adult adiposity in females only. (a) Among a/a offspring, dark-period physical activity in juveniles predicts that in adulthood only in females. Each plot includes 11 LL offspring from 7 litters and 11–12 OL offspring from 8 litters. (b) Adult physical activity predicts adult adiposity, again only in females (same offspring as in panel A). (c) Mediational regression analysis focused on a/a female offspring. Fetal growth restriction predicts adult adiposity (top), but this direct pathway is abrogated when adult physical activity is included in the model (bottom), indicating that induced alterations in physical activity mediate the obesogenic effect of fetal growth restriction. (Analysis includes data on female offspring from panels a & b.)