Metabolic signatures of birth weight in 18 288 adolescents and adults

ABSTRACT Background Lower birth weight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birth weight with a comprehensive metabolic profile measured in adolescents and adults. Methods High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the United Kingdom comprising altogether 18 288 individuals (mean age 26 years, range 15–75). Metabolic associations with birth weight were assessed by linear regression models adjusted for sex, gestational age, and age at blood sampling. The metabolic associations with birth weight were compared to the corresponding associations with adult body mass index (BMI). Results Lower birth weight was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids, and markers of inflammation and impaired liver function (P<0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birth weight resembled the metabolic signature of higher adult BMI ( R 2 =0.77). The resemblance indicated that 1-kg lower birth weight is associated with similar metabolic aberrations as caused by 0.92-units higher BMI in adulthood. Conclusion Lower birth weight is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birth weight and higher adult adiposity suggest potentially shared underlying molecular mechanisms. However, the magnitudes of metabolic associations with birth weight are modest in comparison to the effects of adiposity, implying that birth weight is only a weak indicator of metabolic risk in adulthood. KEY POINTS Lower birth weight is adversely associated with a wide range of established and emerging circulating cardiometabolic biomarkers in adulthood, including lipoprotein subclasses and their lipids, fatty acid balance, amino acids, and markers of inflammation and liver function. The metabolic associations are consistent across a wide age span from adolescence to retirement age, and similar for men and women. The magnitudes of metabolic aberrations are weak for the variation in birth weight observed in general population cohorts. Although the metabolic associations with birth weight are statistically significant, they are likely to be of minor public health relevance. The overall metabolic association pattern with lower birth weight closely resembles the metabolic signature of higher adult adiposity, suggesting that shared underlying metabolic pathways may be involved. 1-kg lower birth weight (≈2 SD) is associated with similar adverse metabolic effects as caused by 0.92 higher BMI (≈0.25 SD) in adulthood. These findings indicate that fetal growth, as assessed by birth weight, only has minor effects on the adult metabolic risk profile in general population settings.