Metabolomic Profiles in Childhood and Adolescence Are Associated with Fetal Overnutrition

Abstract

Fetal overnutrition predisposes offspring to increased metabolic risk. The current study used metabolomics to assess sustained differences in serum metabolites across childhood and adolescence among youth exposed to three typologies of fetal overnutrition: maternal obesity only, gestational diabetes mellitus (GDM) only, and obesity + GDM. We included youth exposed in utero to obesity only (BMI ≥ 30; n = 66), GDM only (n = 56), obesity + GDM (n = 25), or unexposed (n = 297), with untargeted metabolomics measured at ages 10 and 16 years. We used linear mixed models to identify metabolites across both time-points associated with exposure to any overnutrition, using a false-discovery-rate correction (FDR) <0.20. These metabolites were included in a principal component analysis (PCA) to generate profiles and assess metabolite profile differences with respect to overnutrition typology (adjusted for prenatal smoking, offspring age, sex, and race/ethnicity). Fetal overnutrition was associated with 52 metabolites. PCA yielded four factors accounting for 17−27% of the variance, depending on age of measurement. We observed differences in three factor patterns with respect to overnutrition typology: sphingomyelin-mannose (8−13% variance), skeletal muscle metabolism (6−10% variance), and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF; 3−4% variance). The sphingomyelin-mannose factor score was higher among offspring exposed to obesity vs. GDM. Exposure to obesity + GDM (vs. GDM or obesity only) was associated with higher skeletal muscle metabolism and CMPF scores. Fetal overnutrition is associated with metabolic changes in the offspring, but differences between typologies of overnutrition account for a small amount of variation in the metabolome, suggesting there is likely greater pathophysiological overlap than difference.

Keywords: childhood; gestational diabetes mellitus; metabolomics; obesity; pregnancy.

Figure 1

Unadjusted associations (β [95% CI]) of fetal overnutrition (obesity and GDM, obesity only, and GDM only) with metabolite factor scores across 6 years of follow-up among 444 youth in the EPOCH cohort. (A) Longitudinal association fetal overnutrition typology and γ-glutamyl factor scores: offspring of women with obesity only had significantly lower factor scores compared to offspring of women with GDM only. (B) Longitudinal association fetal overnutrition typology and sphingomyelin-mannose factor scores: offspring of women with obesity only had significantly higher factor scores compared to offspring of women with GDM only. (C) Longitudinal association fetal overnutrition typology and skeletal muscle metabolism factor scores: offspring of women with obesity and GDM had significantly higher factor scores compared to offspring of women with GDM only, and offspring of women with obesity only. (D) Longitudinal association fetal overnutrition typology and CMPF factor scores: offspring of women with obesity and GDM had significantly higher factor scores compared to offspring of women with GDM only. Offspring of women with obesity only had significantly higher factor scores compared to women with GDM only. Abbreviations: CMPF, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; GDM, Gestational Diabetes Mellitus; Sphingomyelin, SM; OB, pre-pregnancy obesity. * p < 0.05.

Figure 2

Pearson correlation of offspring clinical metabolic and body composition markers and metabolomic factors at the childhood and adolescent visits. * p < 0.05. (A) Correlations at ~10 years of age. (B) Correlations at ~16 years of age. Abbreviations: CMPF, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; SM, sphingomyelins.