Structure and protection of Cichorium glandulosum polysaccharides against sarcopenic obesity through activating mitophagy via butyrate-GPR43-AMPK pathway.

Sarcopenic obesity (SO) is a major complication of type 2 diabetes with limited therapeutic options. This study characterized CGP-A, a novel branched fructan (6.722 kDa) from Cichorium glandulosum. Its backbone consists of →1)-β-D-Fruf-(2→ and →6)-α-D-Glcp-(1→ residues, interspersed with →1,6)-β-D-Fruf-(2→ branching points. The side chains consist of terminal β-D-Fruf-(2→ units attached to the C-6 position of the fructofuranosyl residues in the backbone. In db/db mice, CGP-A dose-dependently ameliorated insulin resistance, hepatic steatosis, muscle loss and intestinal barrier dysfunction. Importantly, CGP-A significantly improved grip strength, reflecting an enhancement in muscle quality. Integrated multi-omics analysis combining metagenomics, multi-organ proteomics, and metabolomics revealed that CGP-A altered the gut microbiota, specifically enriching Ligilactobacillus, Bacteroides and Alistipes, while elevating serum butyrate. These findings suggest that butyrate may activate the GPR43-AMPK signaling pathway in both liver and skeletal muscle. Hepatic AMPK activation upregulated PPARα to enhance fatty acid oxidation; concurrently, muscular AMPK stimulated PINK1/Parkin-mediated mitophagy, restoring mitochondrial function and attenuating protein degradation. Antibiotic depletion abolished these effects, establishing the microbiota as a crucial mediator. These findings elucidate the gut microbiota-butyrate-GPR43-AMPK pathway through which CGP-A contributes to multi-organ metabolic improvements, offering a promising prebiotic strategy for managing SO.