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Multi-omics Analysis of Metabolic Characteristics and Validation of HBEGF-Mediated Regulatory Mechanisms of Metabolism during Catch-Up Growth in Small-for-Gestational-Age Infants

ABSTRACT: Small-for-gestational-age (SGA) is a globally recognized public health concern. Infants born SGA may experience metabolic disturbances. This study elucidated the key regulatory factors and mechanisms underlying catch-up growth (CUG) and metabolic homeostasis in SGA infants. High-throughput targeted metabolomics were employed to compare the serum profiles of SGA and appropriate-for-gestational-age (AGA) neonates, identifying key metabolic pathways and associated regulatory signaling pathways enriched with differentially expressed metabolites. Animal experiments were conducted, and liver tissue samples were collected from neonatal SGA and AGA rats. Subsequently, mRNA sequencing to identify and analyze differentially expressed genes. HBEGF—a gene critically involved in metabolic processes—was significantly upregulated in SGA rat liver tissues. HBEGF silencing can suppress CUG in SGA rats and influence carbohydrate and lipid metabolism. Furthermore, metabolomic profiling was performed to investigate the role of HBEGF in metabolic regulation during CUG in individuals with SGA. Finally, the impact of HBEGF on the AKT/GSK-3β (protein kinase B/glycogen synthase kinase 3 beta) signaling pathway was explored in both in vivo and in vitro settings. This study confirms metabolic differences between SGA and AGA individuals are evident at early-life. HBEGF may be crucial in CUG progression in SGA by modulating metabolic processes via AKT/GSK-3β signaling pathway.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE313548 | GEO | 2025/12/17

REPOSITORIES: GEO

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Project description:Intrauterine growth restriction is a common cause of small for gestational age (SGA) infants worldwide. SGA infants are deficient in digestive enzymes required for fat digestion and absorption compared to appropriate for gestational age (AGA), putting them at risk for impaired neurocognitive development. The objective was to determine if a hydrolyzed fat (HF) infant formula containing soy free fatty acids, 2-monoacylglycerolpalmitate, cholesterol, and soy lecithin could increase brain tissue incorporation of essential fatty acids or white matter to enhance brain development in SGA and AGA neonatal piglet models. Sex-matched, littermate pairs of SGA (0.5-0.9kg) and AGA (1.2-1.8kg) 2 day old piglets (N=60) were randomly assigned to control (CON) or HF formula diets in a 2 x 2 factorial design. On day 14, 24 piglets were used for hippocampal RNA-sequencing; the rest began a spatial learning task. On days 26-29, brain structure was assessed by magnetic resonance imaging (MRI). Cerebellum and hippocampus were analyzed for fatty acid content. SGA piglets grew more slowly than AGA piglets, with no effect of diet on daily weight gain or weight at MRI. HF diet did not affect brain weight. HF diet increased relative volumes of 7 brain regions and white matter (WM) volume in both SGA and AGA piglets. However, HF did not ameliorate SGA total WM integrity deficits. RNA sequencing revealed SGA piglets had increased gene expression of synapse and cell signaling pathways and decreased expression of ribosome pathways in the hippocampus compared to AGA. HF decreased expression of immune response related genes in the hippocampus of AGA and SGA piglets, but did not correct gene expression patterns in SGA piglets. Piglets learned the T-maze task at the same rate, but SGA HF, SGA CON, and AGA HF piglets had more accurate performance than AGA CON piglets on reversal day 2. HF increased arachidonic acid (ARA) percentage in the cerebellum and total ARA in the hippocampus. HF enhanced brain development in the neonatal piglet measured by brain volume and WM volume in specific brain regions; however, more studies are needed to assess long-term outcomes.

Project description:INTRODUCTION: Restricted or enhanced intrauterine growth is associated with elevated risks of early and late metabolic problems in humans. Metabolomics based on amino acid and carnitine/acylcarnitine profile may have a role in fetal and early postnatal energy metabolism. In this study, the relationship between intrauterine growth status and early metabolomics profile was evaluated.MATERIALS AND METHODS: A single center retrospective cohort study was conducted. Newborn infants were enrolled into the study and they were grouped according to their birth weight percentile as small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) infants. In all infants amino acid and carnitine/acylcarnitine profile with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were recorded and compared between groups.RESULTS: LGA infants had higher levels of glutamic acid and lower levels of ornithine, alanine and glycine (p<0.05) when compared to AGA infants. SGA infants had higher levels of alanine and glycine levels when compared with AGA and LGA infants. Total carnitine, C0, C2, C4, C5, C10:1, C18:1, C18:2, C14-OH and C18:2-OH levels were significantly higher and C3 and C6-DC levels were lower in SGA infants (p<0.05). LGA infants had higher C3 and C5:1 level; and lower C18:2 and C16:1-OH levels (p<0.05). There were positive correlations between free carnitine and phenylalanine, arginine, methionine, alanine and glycine levels (p<0.05). Also a positive correlation between ponderal index and C3, C5-DC, C14, C14:1; and a negative correlation between ponderal index and ornithine, alanine, glycine, C16:1-OH, C18:2 were shown.CONCLUSION: We demonstrated differences in metabolomics possibly reflecting the energy metabolism in newborn infants with intrauterine growth problems in the early postnatal period. These differences might be the footprints of metabolic disturbances in future adulthood.

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Multi-omics Analysis of Metabolic Characteristics and Validation of HBEGF-Mediated Regulatory Mechanisms of Metabolism during Catch-Up Growth in Small-for-Gestational-Age Infants

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