Peptide LKLKLL is a more effective component of Akkermansia muciniphila which regulate glucolipid metabolism through GLP-1/GIP dual modulation

(AKK) to ameliorate metabolic dysfunction has attracted increasing attention as a potential strategy for obesity and diabetes management. Moving beyond the use of live bacteria toward the identification of defined bioactive components may facilitate translational development. In this study, we found that the metabolic supernatant of AKK promoted GLP-1 and GIP secretion in STC-1 cells. Metabolomic profiling identified 54 small molecules in the AKK supernatant, among which a bioactive hexapeptide, LKLKLL, was identified. LKLKLL reduced body weight in high-fat diet-induced obese mice, improved glucose tolerance in diabetic models, enhanced GLP-1 secretion, and reduced GIP levels. Mechanistically, our data suggest that LKLKLL may interact with GPR119 and activate the Gαs/adenylate cyclase/cAMP signaling pathway, leading to increased intracellular Ca²⁺ levels. Together, these findings identify an AKK-derived peptide with GLP-1/GIP regulatory activity and provide a foundation for further investigation of its potential role in metabolic diseases modulation.