Sex-specific effects of maternal dietary carbohydrate quality on fetal development and offspring metabolic phenotype in mice

Abstract

Objectives: In utero glycemia is an important determinant of fetal growth. Women with gestational diabetes are more likely to deliver large-for-gestational age babies that are at increased risk for obesity. The maternal nutritional state modulates the development of offspring biological systems during the critical periods of gestation and lactation. Carbohydrate typically contributes most of the dietary energy, however, there are very few mechanistic studies investigating the effects of maternal dietary carbohydrate quality on fetal and offspring outcomes. Therefore, we sought to investigate the direct effects of maternal carbohydrate quality on sex-specific offspring metabolic programming.

Methods: Female C57BL/6 mice were fed one of five isocaloric diets: four high-sugar diets based on glucose, sucrose, isomaltulose or fructose (all containing 60% energy as carbohydrate), or a standard, minimally processed, chow diet, and were mated with chow-fed males. Half of the dams were sacrificed for fetus dissection and placental collection, with the remaining giving live birth. All dams were metabolically profiled before and during pregnancy, and pups were similarly profiled at 12 weeks of age.

Results: Overall, glucose-fed dams were heavier and fatter than chow or isomaltulose-fed dams. Female fetuses from glucose and isomaltulose-fed mothers weighed less and had smaller livers, than those from chow-fed mothers, with isomaltulose-fed female fetuses also having decreased placental mass. In contrast, male fetuses responded differently to the maternal diets, with heart mass being significantly increased when their mothers were fed fructose-containing diets, that is, sucrose, isomaltulose and fructose. High-sugar fed female offspring weighed the same, but were significantly fatter, than chow-fed offspring at 12 weeks of age, while glucose and isomaltulose-fed male pups displayed a similar phenotype to their mothers'.

Conclusion: While both glucose and isomaltulose diets constrained fetal growth in females, only placentas from isomaltulose-fed dams were significantly smaller than those from chow-fed mothers, suggesting the mechanisms through which fetal growth is reduced may be different. Female fetuses of isomaltulose-fed mothers were also lighter than sucrose-fed fetuses suggesting the glycemic index, or rate of glucose digestion and absorption, may be an important factor in determining nutrient availability to the growing fetus.

Keywords: carbohydrate quality; glycemic index; maternal diet; metabolism; mice.

FIGURE 1

Dam body weight (A) in Part 1 and (B) in Part 2: (i) pre-pregnancy, (ii) at conception, (iii) gained during pregnancy, (iv) during pregnancy. n = 8–10 per diet. Line graphs depict data as mean ± SEM. *p < 0.05 vs. chow; ***p < 0.001 vs. chow; ^##p < 0.01 vs. glucose; ^$p < 0.05 sucrose vs. chow; ¤p < 0.05 isomaltulose vs. chow; § p < 0.05 sucrose vs. isomaltulose; ^⋅p < 0.05 glucose vs. chow; ^⋅⋅⋅p < 0.001 glucose vs. chow; ¶ p < 0.05 glucose vs. fructose; ¶¶ p < 0.01 glucose vs. fructose.

FIGURE 2

Metabolic phenotyping of dams before and during pregnancy (A) in Part 1 and (B) in Part 2: Dam (i) energy expenditure over time, (ii) total energy expenditure, (iii) correlation of energy expenditure and lean mass, (iv) wheel revolutions, (v) respiratory quotient over time, and (vi) mean respiratory quotient over 24 h. n = 8–10 per diet. Line graphs depict data as mean ± SEM. **p < 0.01 vs. chow; ***p < 0.001 vs. chow; ^†p < 0.05 vs. preconception for the same diet.

FIGURE 3

Glucose homeostasis in dams (A) in Part 1 and (B) in Part 2: Dam response to an oral glucose tolerance test before and during pregnancy (i) glucose over time, (ii) glucose AUC, (iii) insulin over time and, (iv) insulin AUC. n = 8–10 per diet. Line graphs depict data as mean ± SEM. *p < 0.05 vs. chow; ^p < 0.05 vs. sucrose; ^ ^p < 0.01 vs. sucrose; ^$p < 0.05 sucrose vs. chow; §§ p < 0.01 sucrose vs. isomaltulose; §§§ p < 0.001 sucrose vs. isomaltulose;^⋅ p < 0.05 glucose vs. chow; ^⋅⋅p < 0.01 glucose vs. chow; ¦p < 0.05 fructose vs. chow; ^†p < 0.05 vs. preconception for the same diet; ^†⁣†p < 0.01 vs. preconception for the same diet.

FIGURE 4

Female and male fetal (A) in Part 1 and (B) in Part 2: (i) body weight, (ii) percentage liver weight, (iii) percentage heart weight and, (iv) placental weight. n = 9–18 per diet per sex. *p < 0.05 vs. chow; **p < 0.01 vs. chow; ***p < 0.001 vs. chow; ^p < 0.05 vs. sucrose; ^##p < 0.01 vs. glucose.

FIGURE 5

Female and male pup (A) in Part 1 and (B) in Part 2: (i) body weight at weaning, (ii) body weight over time from 3 to 12 weeks of age and, (iii) percentage body fat at 12 weeks. n = 7–23 per diet per sex. Line graphs depict data as mean ± SEM. **p < 0.01 vs. chow; ***p < 0.001 vs. chow; ^p < 0.05 vs. sucrose; ¤p < 0.05 isomaltulose vs. chow; § p < 0.05 sucrose vs. isomaltulose; ^⋅p < 0.05 glucose vs. chow; ^⋅⋅p < 0.01 glucose vs. chow; ^⋅⋅⋅p < 0.001 glucose vs. chow; ¶ p < 0.05 glucose vs. fructose; ¶¶ p < 0.01 glucose vs. fructose; ¶¶¶ p < 0.001 glucose vs. fructose.

FIGURE 6

Metabolic phenotyping of female and male pups at 12 weeks of age (A) in Part 1 and (B) in Part 2: Pup (i) energy expenditure over time, (ii) total energy expenditure, (iii) correlation of energy expenditure and lean mass, (iv) wheel revolutions, (v) respiratory quotient over time and, (vi) respiratory quotient. n = 10–26 per diet per sex. Line graphs depict data as mean ± SEM.

FIGURE 7

Glucose homeostasis in pups (A) in Part 1 and (B) in Part 2: Female and male pup response to an oral glucose tolerance test at 12 weeks of age (i) glucose over time, (ii) glucose AUC, (iii) insulin over time and, (iv) insulin AUC. n = 7–21 per diet per sex. Line graphs depict data as mean ± SEM. *p < 0.05 vs. chow; **p < 0.01 vs. chow; ^$$p < 0.01 sucrose vs. chow; ¤p < 0.05 isomaltulose vs. chow; ^⋅p < 0.05 glucose vs. chow; ¦p < 0.05 fructose vs. chow; ¶ p < 0.05 glucose vs. fructose.