The Proteome of Exosomes at Birth Predicts Insulin Resistance, Adrenarche and Liver Fat in Childhood

It is unknown whether there are differentially expressed proteins (DEPs) in the circulating exosomes of appropriate- vs. small-for-gestational-age (AGA vs. SGA) infants, and if so, whether such DEPs relate to measures of endocrine-metabolic health and body composition in childhood. Proteomic analysis in cord-blood-derived exosomes was performed by label-free quantitative mass spectrometry in AGA (n = 20) and SGA infants (n = 20) and 91 DEPs were identified. Enrichment analysis revealed that they were related to complement and coagulation cascades, lipid metabolism, neural development, PI3K/Akt and RAS/RAF/MAPK signaling pathways, phagocytosis and focal adhesion. Protein-protein interaction (PPI) analysis identified 39 DEPs involved in the pathways enriched by the KEGG and Reactome. Those DEPs were associated with measures of adiposity and insulin resistance and with liver fat at age 7 (all <i>p</i> < 0.01). Multivariate linear regression analysis uncovered that two DEPs (up-regulated in SGA), namely PCYOX1 (related to adipogenesis) and HSP90AA1 (related to lipid metabolism and metabolic-dysfunction-associated steatotic liver disease progression), were independent predictors of the hepatic fat fraction at age 7 (β = 0.634; <i>p</i> = 0.002; R² = 52% and β = 0.436; <i>p</i> = 0.009; R² = 24%, respectively). These data suggest that DEPs at birth may predict insulin resistance, adrenarche and/or ectopic adiposity in SGA children at age 7, when an early insulin-sensitizing intervention could be considered.