Akkermansia muciniphila HHAKKα Prevents High‐Fat Diet‐Induced Obesity in Mice via Gut Microbiota Modulation and Regulation of Hepatic Lipid Metabolism

Abstract

Obesity and its associated metabolic disorders pose significant global health challenges. This study investigated the anti-obesity effects of Akkermansia muciniphila HHAKKα in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were administered HHAKKα orally for 8 weeks while maintained on HFD. Results demonstrated that HHAKKα significantly inhibited weight gain (5.76 g vs. 10.79 g in HFD group), with efficacy comparable to orlistat. HHAKKα intervention effectively maintained glucose homeostasis, decreased serum triglycerides and LDL-cholesterol levels, and elevated adiponectin and GLP-1 levels. Furthermore, HHAKKα significantly reduced pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1) and alleviated hepatic steatosis and adipocyte hypertrophy. Mechanistically, HHAKKα modulated gut microbiota composition, increasing beneficial bacteria (Akkermansia, Roseburia, Eubacterium) while decreasing the Bacillota/Bacteroidota ratio by 55.35%. Notably, the HHAKKα intervention significantly enhanced fecal short-chain fatty acids (SCFAs) production-particularly butyrate, which was restored to approximately 1.5 times its normal level-and this effect correlated negatively with serum lipid levels and inflammatory markers. Molecular analysis revealed that HHAKKα regulated hepatic lipid metabolism by inhibiting FASN expression and upregulating PGC-1α. These findings suggest that A. muciniphila HHAKKα ameliorates HFD-induced obesity through a multi-faceted mechanism involving gut microbiota modulation, SCFA production enhancement, inflammation suppression, and hepatic lipid metabolism regulation, highlighting its therapeutic potential for obesity management.