ESPE Abstracts

Introduction: Exosomes are extracellular vesicles whose cargo includes proteins that may influence the function of distant cells. It is unknown, however, whether there are differentially expressed proteins (DEPs) in the circulating exosomes of appropriate- vs small-for-gestational-age (AGA vs SGA) infants at birth and, if so, whether such DEPs relate to measures of endocrine-metabolic health and body composition in childhood.

Subjects and Methods: Proteomic analysis of exosomes (isolated from cord blood at birth) was performed by label-free quantitative mass spectrometry profiling in AGA (n = 20) and SGA infants (n = 20 with spontaneous catch-up). DEPs were identified by bioinformatics analysis including GO annotation, KEGG and Reactome analysis, tissue derivation prediction, and protein-protein interaction (PPI). Pearson correlation analysis screened whether DEPs-at-birth associated with endocrine-metabolic features of postnatal development, in particular with measures of weight gain, adrenarche (circulating DHEAS), insulin resistance (HOMA-IR), and abdominal fat partitioning (subcutaneous, visceral and hepatic fat, by MRI) at age 7 years.

Results: 91 DEPs were detected in AGA vs SGA infants (66 up-regulated, 25 down-regulated in SGA). Enrichment analysis revealed that DEPs related to complement and coagulation cascades, lipid metabolism, neural development, PI3K/AKT and RAS/MAPK signaling pathways, and phagocytosis and focal adhesion. PPI analysis identified 39 DEPs involved in the pathways enriched by KEGG and Reactome. Receiver operating characteristic (ROC) analysis disclosed that 19 of those 39 DEPs distinguished infants by birth weight (BW) with a high degree of confidence (AUC≥0.8, P <0.006). Correlation analysis showed that selected DEPs associated with the Z-score change from BW to BMI at age 7, with HOMA-IR or circulating DHEAS at age 7, and with liver fat at age 7 (all P <0.01). Multivariate linear regression analysis uncovered that two DEPs (both up-regulated in SGA infants), namely PCYOX1 (related to adipogenesis) and HSP90AA1 (related to lipid metabolism and MAFLD progression), were independent predictors of the hepatic fat fraction at age 7 (β=0.634; P = 0.002; R²=52% and β=0.436; P = 0.009; R²=24%, respectively).

Conclusion: At birth, the proteome of circulating exosomes in AGA infants differs markedly from that in SGA infants with catch-up growth. A selection of DEPs-at-birth may become helpful to anticipate insulin resistance and/or ectopic adiposity in SGA children by age 7, when the early initiation of an insulin-sensitising and/or ectopic-fat-reducing intervention could be envisaged.