The Polysaccharide PPS3 From Pumpkin Alleviates High Fat Diet‐Induced Obesity in Mice by Activating the AMPK Signaling Pathway and Regulating the Gut Microbiota

This study evaluated the beneficial effects of pumpkin polysaccharide (PPS3) on diet-induced obesity in mice and explored its underlying mechanisms. In a 10-week study, PPS3 significantly reduced body weight without affecting food or water intake, indicating a direct metabolic effect. PPS3 improved lipid and glucose metabolism by lowering serum triglycerides, total cholesterol, and non-esterified fatty acids, while increasing HDL cholesterol and enhancing glucose tolerance. It also exhibited hepatoprotective effects by reducing hepatic lipid accumulation and mitigating liver damage. Mechanistically, PPS3 activated the AMPK signaling pathway, promoting fatty acid oxidation and lipolysis, while inhibiting lipogenesis via modulation of key regulators such as PPARα, PPARγ, SREBP-1c, and ACC. Additionally, PPS3 modulated gut microbiota diversity and composition, reversing high-fat diet-induced dysbiosis by increasing beneficial genera (Akkermansia and Parabacteroides), lowering the Firmicutes/Bacteroidota ratio, and reducing harmful bacteria linked to obesity. Metabolomic analysis revealed enrichment of metabolites like 18β-Glycyrrhetinic acid and nonanoic acid, which may contribute to anti-obesity effects. PPS3 also significantly modulated amino acid and lipid metabolism, promoting metabolic homeostasis. These findings highlight PPS3 as a promising beneficial agent with translational potential for obesity management, supporting further clinical investigation to address metabolic disorders in humans.