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

Ling ZhangZhou PengCaiyu LinHaixia HuJuan DuSiqi HuangShan Huang^*Jianfang Gao^*Xirong Guo^*

• Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China

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-α 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.