1. Academic Validation
  2. A novel natural PPARγ agonist, Gypenoside LXXV, ameliorates cognitive deficits by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice

A novel natural PPARγ agonist, Gypenoside LXXV, ameliorates cognitive deficits by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice

  • Phytother Res. 2022 Apr;36(4):1770-1784. doi: 10.1002/ptr.7413.
Xiangbao Meng 1 2 Yuan Zhang 2 Zongyang Li 2 Jinxian Hu 2 Di Zhang 2 Weiwei Cao 2 Min Li 3 Guoxu Ma 4 Sicen Wang 5 Ping Cui 6 Qian Cai 1 Guodong Huang 2
Affiliations

Affiliations

  • 1 College of Pharmacy, Jinan University, Guangzhou, China.
  • 2 Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Institute of Translational Medicine, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
  • 3 School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong, China.
  • 4 Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 5 School of Medicine, Xi'an Jiaotong University, Xi'an, China.
  • 6 Department of Pharmacy, Shenzhen Children's Hospital, Shenzhen, China.
Abstract

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 18 F-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.

Keywords

PPARγ; glucose transporter 4; insulin resistance; microPET; type 2 diabetes mellitus.

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