Imidazole propionate ameliorates lipid metabolism in adipocytes to attenuate high-fat diet-induced obesity via PPAR signaling pathway.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.