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Human Milk-Derived 5′-UMP Promotes Thermogenesis and Mitochondrial Biogenesis to Ameliorate obesity

ABSTRACT:

Background: Traditional obesity interventions are often unsuitable for children. Breastfeeding has been shown to reduce obesity risk, potentially through bioactive metabolites in human milk. Here, we identified a human milk-derived metabolite, uridine 5'-monophosphate (5'-UMP), whose role in lipid metabolism and thermogenesis remains largely unknown. Methods: Untargeted metabolomics was performed on colostrum samples from obese and healthy mothers to identify obesity-associated metabolites. Zebrafish larvae and human preadipocytes were used to evaluate the anti-obesity effects of 5'-UMP. Lipid accumulation was assessed by Oil Red O and Nile Red staining, while mitochondrial function was analyzed using transgenic zebrafish (Tg(Xla.Eef1a1: mlsEGFP)) and fluorescent imaging. Results: Pyrimidine metabolism was significantly enriched in obese mothers, with orotate and 5'-UMP levels altered. Targeted analysis confirmed the presence of 5'-UMP in colostrum. Zebrafish toxicity assays confirmed 5'-UMP safety up to 200 µM. In the high-fat diet-induced zebrafish obesity model, 5'-UMP treatment significantly reduced abdominal lipid accumulation. In adipocytes, 5'-UMP enhanced mitochondrial respiration and increased mRNA and protein expression of PGC1-a and UCP1. Furthermore, mitochondrial fluorescence intensity and protein levels of NRF1 and MFN2 were elevated, indicating enhanced mitochondrial biogenesis and activity. Conclusion: Maternal obesity is associated with changes in the human milk metabolome. 5'-UMP, a nucleotide metabolite enriched in human milk, promotes thermogenesis and mitochondrial activation, effectively ameliorating obesity in zebrafish and human adipocytes. These findings support its potential as a safe, milk-derived therapeutic candidate for pediatric obesity intervention.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - negative - HILIC, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS13027 | MetaboLights | 2025-09-23

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13027_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13027_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13027_LC-MS_positive_reverse-phase_metabolite_profiling-1.txt	Txt
	a_MTBLS13027_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Project description:Background: Maternal pre-pregnancy BMI is a critical factor influencing the composition of breast milk. Breast milk has abundant extracellular vesicles (EVs) containing various biological molecules (cargo), including miRNAs. EVs are not degraded in the gastrointestinal system and circulation; thus, breast milk EVs (bEVs) interact with other organs in breastfed infants and modify the gene expression of recipient cells using miRNAs. In maternal obesity, miRNAs in bEVs are deregulated, which might be associated with adverse health outcomes in infants. In this study, we examined 798 miRNAs to determine which miRNAs are altered in the bEVs of obese mothers and their potential impact on breastfed infants. Methods: We recruited healthy nursing mothers who were either obese (BMI≥30) or lean (BMI<25) based on their pre-pregnancy BMI, and delivered a singleton baby in the prior six months. EVs were isolated from breast milk with ultracentrifugation. bEV characteristics were examined by flow cytometry and fluorescence imaging of EV markers. A total of 798 miRNAs were screened using a NanoString human miRNA panel to find deregulated miRNAs in bEVs of obese mothers compared to lean mothers. Results: We included 65 nursing mothers: 47 lean and 18 obese mothers based on pre-pregnancy BMI. After bEV isolation, we confirmed the expression of general EV markers. Out of 37 EV markers, CD326 was the most highly expressed marker in bEVs. From miRNA analysis using NanoString, we found that the most abundant miRNAs include miR-30b-5p, miR-494-3p, and let-7 families, and the list of top 10 miRNAs was not different between lean and obese mothers. Target genes of the top 10 miRNAs were associated with the EGFR, ErbB, and FoxO signaling pathway. Nineteen miRNAs were deregulated in bEVs of obese mothers (adjusted p < 0.05 cut-off), including miR-575, miR-548g-3p, miR-582-3p, and miR-652-5p. The target genes of these miRNAs are associated with lipid metabolism, inflammatory diseases, and nervous/cardiovascular system development. Conclusion: In this study, we demonstrated altered miRNAs in bEVs of obese mothers and identified the pathways of their potential target genes. Our findings will provide insight for future studies investigating the role of bEVs in breastfed infants.

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Human Milk-Derived 5′-UMP Promotes Thermogenesis and Mitochondrial Biogenesis to Ameliorate obesity

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