LAUSR

Targeting the PPARγ might be a potential therapeutic strategy for diabetes‐associated cognitive decline (DACD). In this study, Gypenoside LXXV (GP‐75), a dammarane‐type triterpene compound isolated from Gynostemma pentaphyllum, was found to be a novel PPARγ agonist using a dual‐luciferase reporter assay system. However, whether GP‐75 has protective effects against DACD remains unknown. Interestingly, intragastric administration of GP‐75 (40 mg/kg/day) for 12 weeks significantly attenuated the cognitive deficit in db/db mice. GP‐75 treatment significantly improved the glucose tolerance and lipid metabolism, and suppressed neuroinflammation. Notably, GP‐75 treatment dramatically increased the uptake of glucose by the brain, as detected by 18F‐FDG PET. Incubation of primary cortical neurons with GP‐75 significantly increased 2‐deoxyglucose uptake. In addition, GP‐75 treatment markedly increased the p‐Akt (Ser 473)/total Akt levels and the expression levels of PPARγ and GLUT4, while decreasing the levels of p‐IRS‐1 (Ser 616)/total IRS‐1. Importantly, all of these protective effects mediated by GP‐75 were abolished by cotreatment with the PPARγ antagonist, GW9662. However, GP‐75‐mediated PPARγ upregulation was not affected by coincubation with the phosphatidylinositol 3‐kinase inhibitor, LY294002. Collectively, GP‐75 might be a novel PPARγ agonist that ameliorates cognitive deficit by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice.