Multi-omics strategies combined with molecular docking to explore the regulatory effects of licochalcone A on glycolipid metabolism in db/db mice

Licochalcone A (LicA) is a flavonoid compound extracted from licorice. LicA has the function of regulating blood sugar and has been proven to be related to the intestinal flora, but its mechanism remains unclear. This study investigated the effect of LicA on improving insulin resistance and glycolipid metabolism in type 2 diabetic mellitus (T2DM) mice. A T2DM model was established using db/db mice. We found that LicA could effectively reduce insulin resistance and fat deposition in T2DM mice, alleviate liver inflammation, improve the integrity of the intestinal barrier, and reduce endotoxins in the circulation. Further studies on 16S rRNA have shown that LicA regulates the composition of the intestinal flora in T2DM mice and reduces the abundance of the genus p-75-a5. The combined analysis of liver metabolomics and liver proteomics indicated that LicA altered the intestinal microbiota metabolite hypotaurine through p-75-a5, and hypotaurine played a bridging role between p-75-a5 and glycolipid metabolism in T2DM. Through multi-omics joint analysis and WB experimental verification, the results showed that LicA activates the PPAR signaling pathway to improve glucose lipid metabolism disorders in T2DM. More importantly, after treating db/db mice with antibiotics, the beneficial effects of LicA were blocked, indicating that the gut microbiota plays a key role in LicA's improvement of glucose and lipid metabolism in T2DM. In conclusion, this study revealed a new mechanism by which LicA improves T2DM glucose and lipid metabolism disorder, and the potential improvement of LicA's glucose and lipid metabolism in T2DM may be related to the change of p-75-a5 targeting hypotaurine.