Journal
PHYTOTHERAPY RESEARCH
Volume 36, Issue 4, Pages 1770-1784Publisher
WILEY
DOI: 10.1002/ptr.7413
Keywords
glucose transporter 4; insulin resistance; microPET; PPAR gamma; type 2 diabetes mellitus
Categories
Funding
- China Postdoctoral Science Foundation [2021M702285]
- Guangdong Innovation Platform of Translational Research for Cerebrovascular Diseases
- National Natural Science Foundation of China [81503290, 81772685, 81902522, 81760227, 8170355]
- Natural Science Foundation of Guangdong Province [2018A030310647, 2019A1515010311]
- Shenzhen Double Chain Grant [[2018]256]
- Basic research projects (subject arrangement) of Shenzhen Science and Technology Program [JCYJ20170413173149177, JCYJ20180507184656626]
- Research Fund from Shenzhen Key Laboratory of Neurosurgery [ZDSYS20140509173142601]
- Shenzhen Development and Reform Commissions Stroke Screening and Prevention Public Service Platform improving program
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This study suggests that Gypenoside LXXV (GP-75) from Gynostemma pentaphyllum may be a novel PPAR gamma agonist that has the potential to improve diabetes-associated cognitive decline. GP-75 treatment enhances brain glucose uptake, improves glucose tolerance and lipid metabolism, and suppresses neuroinflammation, leading to attenuation of cognitive deficits.
Targeting the PPAR gamma 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 PPAR gamma 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 F-18-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 PPAR gamma 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 PPAR gamma antagonist, GW9662. However, GP-75-mediated PPAR gamma upregulation was not affected by coincubation with the phosphatidylinositol 3-kinase inhibitor, LY294002. Collectively, GP-75 might be a novel PPAR gamma agonist that ameliorates cognitive deficit by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice.
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