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

Abstract

Targeting the PPARγ might be a potential therapeutic strategy for diabetesassociated 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

Increasing brain glucose uptake by Gypenoside LXXV ameliorates cognitive deficits in a mouse model of diabetic Alzheimer's disease

“…We have previously shown that GP‐75 exerted antidiabetic effects in db/db mice (Meng et al, 2022). In this study, the fasting glucose levels of APP/PS1xdb/db mice were significantly higher than those of db/m and APP/PS1 mice at all time points ( p < 0.01, Figure 2a).…”

“…In this study, the fasting glucose levels of APP/PS1xdb/db mice were significantly higher than those of db/m and APP/PS1 mice at all time points ( p < 0.01, Figure 2a). We have previously reported that the intragastric administration of GP‐75 (40 mg/kg/day) reached a maximum anti‐diabetic effect on db/db mice at 3 months of administration (Meng et al, 2022). In this study, with rosiglitazone as a positive control, the fasting glucose levels were significantly reduced in APP/PS1xdb/db mice following the intragastric administration of GP‐75 (40 mg/kg/day) for 3 months ( p < 0.01, Figure 2a).…”

“…Resistant neurons were analyzed by western blot to confirm GLUT4 overexpression. We have previously reported that exposure of neurons to GP‐75 (20 μM) for 12 h increased GLUT4 expression, which was abrogated by cotreatment with GW9662 (10 μM) or LY294002 (20 μM) (Meng et al, 2022). Therefore, in this study, cultured hippocampal neurons transfected with lenti‐GFP‐GLUT4 were treated with GP‐75 (20 μM), either alone or in combination with GW9662 (10 μM) or LY294002 (20 μM).…”

“…Glucose transporter 4 (GLUT4) is an insulin‐sensitive glucose transporter predominantly expressed in hippocampal neurons (Batty & Langlais, 2021). We have previously reported that defective cerebral insulin signaling and decreased GLUT4 expression occur in diabetic mice carrying a homozygous mutation in the leptin receptor gene (db/db) and APP/PS1 mice (Li et al, 2021; Meng et al, 2022). Thus, the downregulation of GLUT4 leading to cerebral glucose hypometabolism represents an early event during the pathogenesis of T2DM and AD.…”

“…We have previously reported that Gypenoside XVII, a saponin isolated from Gynostemma pentaphyllum , attenuates cognitive deficits in APP/PS1 mice (Meng et al, 2014; Meng et al, 2016). We also found that a novel natural PPARγ agonist isolated from Gynostemma pentaphyllum , Gypenoside LXXV (GP‐75), ameliorates cognitive impairment via upregulation of GLUT4 in db/db mice (Meng et al, 2022). GP‐75 is also an enzymatic biotransformation product of Gypenoside XVII (Cui et al, 2017).…”