Obesity is a global health concern linked to metabolic disorders and gut microbiota dysbiosis, particularly under high-fat diet (HFD) conditions. This study explores the role of imidazole propionate (ImP), a histidine-derived microbial metabolite, in regulating lipid metabolism and the development of obesity. Male C57BL/6 mice were fed either a chow diet or HFD for 15 weeks, followed by plasma metabolomic analysis, which revealed significant downregulation of ImP in obese mice. Functional assays were performed using zebrafish larvae and human adipocytes, with lipid accumulation assessed via Nile Red and Oil Red O staining. Transcriptomic sequencing and KEGG pathway analysis were used to investigate the underlying molecular mechanisms. ImP treatment notably reduced lipid accumulation in both zebrafish larvae and human adipocytes. RNA-seq and protein expression analyses revealed that ImP suppressed peroxisome proliferator-activated receptor (PPAR) pathway key components, such as FABP4, ACSL4, and CEBPα. These findings demonstrate that ImP attenuates lipid accumulation by inhibiting the PPAR signaling pathway. As a gut microbial metabolite, ImP may offer therapeutic potential in preventing or treating HFD-induced 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-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.