Population-based plasma lipidomics reveals developmental changes in metabolism and signatures of obesity risk: a mother-offspring cohort study

Abstract

Background: Lipids play a vital role in health and disease, but changes to their circulating levels and the link with obesity remain poorly characterized in expecting mothers and their offspring in early childhood.

Methods: LC-MS/MS-based quantitation of 480 lipid species was performed on 2491 plasma samples collected at 4 time points in the mother-offspring Asian cohort GUSTO (Growing Up in Singapore Towards healthy Outcomes). These 4 time points constituted samples collected from mothers at 26-28 weeks of gestation (n=752) and 4-5 years postpartum (n=650), and their offspring at birth (n=751) and 6 years of age (n=338). Linear regression models were used to identify the pregnancy and developmental age-specific variations in the plasma lipidomic profiles, and their association with obesity risk. An independent birth cohort (n=1935), the Barwon Infant Study (BIS), comprising mother-offspring dyads of Caucasian origin was used for validation.

Results: Levels of 36% of the profiled lipids were significantly higher (absolute fold change > 1.5 and Padj < 0.05) in antenatal maternal circulation as compared to the postnatal phase, with phosphatidylethanolamine levels changing the most. Compared to antenatal maternal lipids, cord blood showed lower concentrations of most lipid species (79%) except lysophospholipids and acylcarnitines. Changes in lipid concentrations from birth to 6 years of age were much higher in magnitude (log2FC=-2.10 to 6.25) than the changes observed between a 6-year-old child and an adult (postnatal mother) (log2FC=-0.68 to 1.18). Associations of cord blood lipidomic profiles with birth weight displayed distinct trends compared to the lipidomic profiles associated with child BMI at 6 years. Comparison of the results between the child and adult BMI identified similarities in association with consistent trends (R2=0.75). However, large number of lipids were associated with BMI in adults (67%) compared to the children (29%). Pre-pregnancy BMI was specifically associated with decrease in the levels of phospholipids, sphingomyelin, and several triacylglycerol species in pregnancy.

Conclusions: In summary, our study provides a detailed landscape of the in utero lipid environment provided by the gestating mother to the growing fetus, and the magnitude of changes in plasma lipidomic profiles from birth to early childhood. We identified the effects of adiposity on the circulating lipid levels in pregnant and non-pregnant women as well as offspring at birth and at 6 years of age. Additionally, the pediatric vs maternal overlap of the circulating lipid phenotype of obesity risk provides intergenerational insights and early opportunities to track and intervene the onset of metabolic adversities.

Clinical trial registration: This birth cohort is a prospective observational study, which was registered on 1 July 2010 under the identifier NCT01174875 .

Keywords: Adiposity; Development; Gestation; Intergenerational; Lipidomics; Lipids and fatty acids; Maternal-fetal; Metabolomics.

Conflict of interest statement

NK and YSC are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, EVOLVE Biosystems, DSM, and Danone. All other authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Temporal and developmental alterations to the circulatory lipids in the GUSTO cohort: A Antenatal and postnatal plasma collection time points for mother-offspring dyads in GUSTO cohort. B PCA plot of lipidomics data (n=2491). C Postnatal vs. antenatal changes in maternal lipidomic profiles. D Comparison of maternal antenatal plasma with cord blood (CB) lipidomic profiles. E Changes in child lipidomic profiles between birth and 6 years of age. F Comparison of pediatric (6-year-old child) and adult (postnatal mothers) plasma lipidomes. The most significant lipid species based on adjusted p-values are labeled in c-f. Effect size is shown as log2 of fold change. Error bars indicate 95% confidence interval. Diamond—Padj ≥ 0.05 or |FC|≤1.5 (gray), circle—Padj <0.05 and |FC|>1.5, and square—Padj <1.00E−10 and |FC|>1.5

Fig. 2

Association of maternal and child adiposity with plasma lipidomic profiles: A Association of pre-pregnancy BMI with antenatal plasma lipidome (pregnant state). B Association of maternal BMI with postnatal plasma lipidome (non-pregnant state). C Association of birth weight (BW) with cord blood plasma lipidome. D Association of child BMI with plasma lipidome at 6 years of age. The top 20 lipid species with the directionality of association (10 positive and 10 negative) with adiposity measures in each study group are shown in volcano plots. The horizontal dotted line indicates Padj=0.05 in each volcano plot. Effect sizes are shown as % change in lipid concentration per unit change in BMI, or per 100 g change in birth weight. Error bars indicate 95% confidence interval. Diamond—Padj ≥ 0.05 (gray), circle—Padj <0.05, and square—Padj <1.00E−5 in forest plots

Fig. 3

Comparison of plasma lipidomic profiles associated with mother and child adiposity: A Pie chart comparing the percent overlap and directionality of association in the four studies. B Venn-diagram of lipids species that passed significance in the four association studies. C Effect sizes of 41 lipid species that overlapped between the four studies

Fig. 4

Replication of GUSTO identified ppBMI and BW lipid signatures in Barwon Infant Study (BIS). A Sample collection at two time points. B PCA plot of lipidomics data (n=1935). C Association of pre-pregnancy BMI (ppBMI) with antenatal plasma lipidome. D Scatter plot of effect sizes in GUSTO and BIS for ppBMI study. E Association of birth weight (BW) with cord blood plasma lipidome. The most significant lipid species based on adjusted p-values are labeled in C and E. Effect sizes are shown as % change in lipid concentration per unit change in BMI, or per 100 g change in birth weight. Error bars indicate 95% confidence interval. Diamond—Padj ≥ 0.05 (gray), circle—Padj <0.05, and square—Padj <1.00E−5. F Scatter plot of effect sizes in GUSTO and BIS for BW study. Red—significant in both cohorts, purple—only significant in GUSTO, yellow—only significant in BIS, and gray—not significant in both cohorts