Pre-gestational vs gestational exposure to maternal obesity differentially programs the offspring in mice

Abstract

Aims/hypothesis: Maternal obesity is associated with an increased risk of obesity and impaired glucose homeostasis in offspring. However, it is not known whether a gestational or pre-gestational exposure confers similar risks, and if so, what the underlying mechanisms are.

Methods: We used reciprocal two-cell embryo transfers between mice fed either a control or high-fat diet (HFD) starting at the time of weaning. Gene expression in placenta was assessed by microarray analyses.

Results: A pre-gestational exposure to a maternal HFD (HFD/control) impaired fetal and placental growth despite a normal gestational milieu. Expression of imprinted genes and genes regulating vasculogenesis and lipid metabolism was markedly altered in placenta of HFD/control. An exposure to an HFD (control/HFD) only during gestation also resulted in fetal growth restriction and decreased placental weight. Interestingly, only a gestational exposure to an HFD (control/HFD) resulted in obesity and impaired glucose tolerance in adulthood.

Conclusions/interpretation: An HFD during pregnancy has profound consequences for the offspring later in life. Our data demonstrate that the mechanism underlying this phenomenon is not related to placental dysfunction, intrauterine growth restriction or postnatal weight gain, but rather an inability of the progeny to adapt to the abnormal gestational milieu of an HFD. Thus, the ability to adapt to an adverse intrauterine environment is conferred prior to pregnancy and it is possible that the effects of a maternal HFD may be transmitted to subsequent generations.

Fig. 1

Female (a, c) and male (b, d) fetal (a, b) and placental (c, d) weight (black bars, E12.5; grey bars, E17.5) normalised to C/C and expressed as means±SEM. *p<0.05 vs C/C at E12.5; ^†p<0.05 vs C/C at E17.5. Six C and five HFD litters at each age. (e) Labyrinth/placenta ratios and (f) placenta/(placenta+decidua) ratios. n=6–8 placentas from each group. Data are expressed as means±SEM. *p<0.05 vs C/C. C, control

Fig. 2

F:P weight ratios were calculated for female (a) and male (b) mice for each group (black bars, E12.5; grey bars, E17.5). *p<0.05 vs C/C at E12.5; ^†p<0.05 vs C/C at E17.5. Six C and five HFD litters at each age. C, control; F/P, fetal/placental

Fig. 3

Newborn weights. Six control and five HFD litters. Repeated measures were performed on individual animals from 2–13 weeks of age. (*p<0.05, **p<0.01, ****p<0.0001). The horizontal lines through the data points represent the mean

Fig. 4

Adult weight and percentage body fat. Female (a) and male (b) offspring were weighed weekly. Repeated measures were performed on individual animals from 2– 13 weeks of age. Black circles, HFD/HFD; triangles, C/HFD; squares, HFD/C; diamonds, C/C. Percentage body fat (c, d) and leptin levels (e, f) of female (c, e) and male (d, f) progeny at 13 weeks of age. Data are expressed as means±SEM. *p<0.05 C/HFD vs C/C; ^†p<0.05 HFD/HFD vs C/C. C, control

Fig. 5

Metabolic abnormalities in 13-week-old offspring. 2 h glucose tolerance tests in females (a) and males (b). Black circles, HFD/HFD; triangles, C/HFD; squares, HFD/C; diamonds, C/C. AUC_glucose in females (c) andmales (d). Fasting plasma insulin levels in females (e) and males (f). Fasting hepatic triacylglycerol levels in females (g) and males (h). Data are expressed as means±SEM. *p<0.05 vs C/C. C, control

Fig. 6

Placental gene expression patterns. Gene expression was measured by quantitative PCR in placenta at E12.5 (black bars) and E17.5 (grey bars). n=7–11. Fold change values for each time point are relative to C/C and normalised to Gapdh. *p<0.05 vs C/C at each age. C, control