Introduction: The perinatal period is highly sensitive to obesogenic determinants, and it is consistently reported that adverse birth outcomes are among the most important early risk factors for childhood obesity. Nevertheless, the molecular mechanisms underpinning this greater predisposition remain to be elucidated.

Methods: To obtain deeper insights into the influence of neonatal conditions in obesity-related metabolic disturbances occurring later during childhood, we applied high-throughput metabolomics (UHPLC-HRMS) to plasma and erythrocyte samples from a cohort of children diagnosed with obesity, from whom birth metrics (i.e., gestational age, weight, and length at birth) were available from their medical records.

Results: The findings of this study evidenced that adverse neonatal outcomes (i.e., low gestational age, weight, and length at birth) may predispose individuals to an unhealthier metabolic status, as reflected in negative associations with anthropometric parameters (e.g., waist circumference) and biochemical markers of insulin resistance (e.g., HOMA-IR) and inflammation (e.g., CRP, inflammatory indices). This was accompanied by exacerbations in a multitude of central metabolic pathways that play a crucial role in obesity pathophysiology, such as energy metabolism, the homeostasis of branched chain and aromatic amino acids, the regulation of oxidative stress, and the biosynthesis of steroid hormones and bile acids.

Conclusion: Accordingly, we hypothesize that even minor variations in neonatal conditions may provoke deleterious molecular programming mechanisms with a strong impact on later metabolic risk.