Mucin alleviates HFD-induced obesity and MASLD via an Akkermansia muciniphila-associated mucin-Neu5Ac-PPARα signaling axis

Mucin is known to modulate the gut environment; however, its specific mechanisms and downstream metabolites in alleviating obesity and hepatic steatosis remain unclear. In this study, we investigated the beneficial effects of mucin in a high-fat diet (HFD) mouse model and explored the underlying mechanisms. Our results showed that mucin supplementation significantly reduced weight gain, improved glucose tolerance, and alleviated hepatic steatosis and fibrosis in HFD-fed mice. These benefits were abolished by antibiotic treatment, indicating a microbiota-dependent mechanism. Fecal 16S rRNA gene sequencing and metabolomics revealed that mucin specifically enriched the abundance of Akkermansia muciniphila, which enzymatically liberates N-acetylneuraminic acid (Neu5Ac) from mucin O-glycan via glycoside hydrolases, leading to elevated fecal and serum Neu5Ac levels. Direct administration of Neu5Ac successfully recapitulated the protective effects of mucin, reducing obesity, improving insulin sensitivity, and preserving colonic mucosal integrity. Mechanistically, mucin and Neu5Ac improve lipid homeostasis by promoting fatty acid oxidation via the PPARα/CPT1A pathway. In conclusion, our findings demonstrate that mucin alleviates HFD-induced metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD) by enriching A. muciniphila and subsequent Neu5Ac production. The Neu5Ac-PPARα/CPT1A axis represents a promising therapeutic target for treating obesity and associated liver pathologies.