Human milk-derived 5'-UMP promotes thermogenesis and mitochondrial biogenesis to ameliorate obesity.

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- 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.