Probiotics‐derived postbiotics improve host metabolic syndrome by activating the adipocyte thermogenic signaling pathway in high‐fat diet‐fed mice

Metabolic syndrome, including type 2 diabetes mellitus (T2DM) and obesity, represents a global health challenge. While probiotics can modulate host metabolism, postbiotics (inanimate microbial preparations) have emerged as potentially safer and more stable therapeutic alternatives. The current study investigates the effects of postbiotics derived from five human‐origin bacterial strains in mice model with high‐fat diet‐induced metabolic syndrome. Using multi‐omics profiling, we demonstrate that supplementation of postbiotics significantly ameliorates weight gain, improves glucose tolerance and insulin sensitivity, and alleviates hepatic steatosis. Transcriptomic analysis indicates that the treatment upregulated adipocyte genes related to thermogenesis and fatty acid oxidation while downregulating hepatic lipid synthesis. Most importantly, the intervention reshapes the gut microbiota structure. Target metabolomics reveals that this microbial remodeling is accompanied by a significant elevation of indole‐3‐acetic acid (IAA), a tryptophan‐derived microbial metabolite, in the host serum. Functional studies in primary adipocytes confirm that IAA is sufficient to trigger thermogenic gene expression and activate AMP‐activated protein kinase (AMPK) signaling. These findings suggest a mechanism where postbiotics improve metabolic health by modulating the gut ecosystem to enrich beneficial metabolites like IAA, which in turn ameliorates the metabolic syndrome and promotes adipocyte thermogenesis and lipolysis. The present research supports postbiotics as a promising therapeutic strategy for metabolic syndrome and highlights the importance of the gut microbiota‐metabolite axis.