Ontogeny of circulating lipid metabolism in pregnancy and early childhood – a longitudinal population study

Abstract

Background: There is mounting evidence that in utero and early life exposures may predispose an individual to metabolic disorders in later life; and dysregulation of lipid metabolism is critical in such outcomes. However, there is limited knowledge about lipid metabolism and factors causing lipid dysregulation in early life that could result in adverse health outcomes in later life. We studied the effect of antenatal factors such as gestational age, birth weight and mode of birth on lipid metabolism at birth; changes in the circulating lipidome in the first four years of life and the effect of breastfeeding in the first year of life. From this study, we aim to generate a framework for deeper understanding into factors effecting lipid metabolism in early life, to provide early interventions for those at risk of developing metabolic disorders including cardiovascular diseases. Methods and findings: We performed comprehensive lipid profiling of 1074 mother-child dyads in the Barwon Infant Study (BIS), a population based pre-birth cohort and measured 776 distinct lipid species across 42 lipid classes using ultra high-performance liquid chromatography (UHPLC). We measured lipids in 1032 maternal serum samples at 28 weeks' gestation, 893 cord serum samples at birth, 793, 735, and 511 plasma samples at six, twelve months, and four years, respectively. The lipidome differed between mother and newborn and changed markedly with increasing child's age. Cord serum was enriched with long chain poly-unsaturated fatty acids (LC-PUFAs), and corresponding cholesteryl esters relative to the maternal serum. Alkenylphosphatidylethanolamine species containing LC-PUFAs increased with child's age, whereas the corresponding lysophospholipids and triglycerides decreased. We performed regression analyses to investigate the associations of cord serum lipid species with antenatal factors: gestational age, birth weight, mode of birth and duration of labor. Majority of the cord serum lipids were strongly associated with gestational age and birth weight, with most lipids showing opposing associations. Each mode of birth showed an independent association with cord serum lipids. Breastfeeding had a significant impact on the plasma lipidome in the first year of life, with upto 17-fold increases in a few species of alkyldiaclylglycerols at 6 months of age. Conclusions: This study sheds light on lipid metabolism in infancy and early childhood and provide a framework to define the relationship between lipid metabolism and health outcomes in early childhood. Funding Statement: This work was supported by the A*STAR-NHMRC joint call funding (1711624031).

Early life infection and proinflammatory, atherogenic metabolomic and lipidomic profiles in infancy: a population-based cohort study

“…Plasma was stored at –80°C, and aliquots were shipped on dry ice to Nightingale Health (Helsinki, Finland) for NMR metabolomic quantification and Baker IDI (Melbourne, Australia) for liquid chromatography/mass spectrometry (LC/MS) lipidomic quantification, as described below. For secondary analyses investigating possible ‘reverse causality’, that is, whether metabolomic or lipidomic profile at birth was associated with number of parent-reported infections from birth to 6 months of age, metabolomics and lipidomics data using the same platforms from venous cord blood collected at birth, as previously described ( Burugupalli et al, 2022 ; Mansell et al, 2021 ), was used.…”

Metabolic impact of adipose tissue macrophages in the early postnatal life

“…ATMs in the newborn mouse express lysophosphatidylcholine acyltransferase 2 (LPCAT2), which converts AKGs into PAF and lacks the AKG degrading enzyme, AKG‐monooxygenase (AGMO) (Table 1). Accordingly, alkyldiacylglcyerols and alkenylphosphatidylethanolamine are enriched in the adipose tissue of breastfed infants 120 . After the first year of age, the adipose tissue level of the AKG‐related lipid species does not correlate with the length of breastfeeding, 120 and the adult adipose tissue expresses AKG monooxygenase, which breaks down AKGs to free fatty acids 13 .…”

The Role of Human Milk Lipids and Lipid Metabolites in Protecting the Infant against Non-Communicable Disease

“…The lipokine 12,13-dihydroxyoctadecanoic acid (12,, is a metabolite of linoleic acid, produced in adipose tissue by the action of CYP2 and epoxide hydrolase enzymes (Figure 2C). It is released from adipose tissue in response to exercise and cold exposure [61].…”

“…Moreover, a more complex analysis of the plasma lipidome of breastfed infants at three months of age identified lower total phosphatidylcholines (PC), lower short chain unsaturated fatty acid containing-PC, higher long chain polyunsaturated fatty acid containing- PC, higher cholesterol esters and differing sphingomyelin compared to infants who were not breastfed [ 9 ]. There is emerging evidence that breastfeeding significantly impacts the plasma lipidome through the first year of life, with some circulating lipid species, such as alkyldiacylglcyerols, present up to 17 times higher in those who were breastfed [ 12 ]. Although the exact effects of this on future disease risk remains unclear, prolonged breastfeeding duration is overall related to a healthier plasma lipidome in childhood and through teenage years.…”

“…There is increasing evidence of the importance of lipids in human health and given the differences between human milk and infant formula lipid composition, as well as differences in the blood lipidome of breastfed and formula-fed infants, the lack of exposure to the human milk lipidome may contribute to metabolic dysfunction and the higher risk of NCD observed in formula-fed infants. As such, human milk lipidomic analyses are a promising approach to investigate protection against obesity, inflammation and later NCD [ 9 , 10 , 11 , 12 ]. There are several mechanisms through which bioactive lipid species may protect the newborn infant against NCD risk.…”