Postbiotic-Mediated Obesity Reduction via Bioactive Peptide ETLVK and Gut Microbiota in HFD Mice

Although Lactiplantibacillus plantarum (L. plantarum) TCCC11824 (CGMCC 8198) has shown antiobesity effects, its active components remained unclear. This study reveals that the L. plantarum TCCC11824 crushed supernatant (LpS) exerts broad antiobesity activities in high-fat diet (HFD)-induced obese mice. LpS significantly improved blood lipid profiles, reduced hepatic injury, and suppressed inflammation in liver and epididymal fat. It also mitigated ectopic fat accumulation and modulated gut microbiota composition, contributing to improved metabolic health. Mechanistic studies identified that the 3–10 kDa ultrafiltration fraction of LpS strongly inhibited pancreatic cholesterol esterase and lipase in vitro and suppressed HMGCR expression in lipid-disordered cells. Bioinformatics analysis predicted five candidate bioactive peptides (IPR, IEK, PGDR, ETLVK, and QAEQLR) from the full-length protein sequence. Among them, LC–MS/MS confirmed that ETLVK was a key peptide responsible for the lipid-lowering effect. This work uncovers a multitarget mechanism by which L. plantarum TCCC11824 mediates antiobesity activity through microbial-derived peptides, offering new insights into probiotic-based metabolic regulation.