To address this question the present study
To address this question, the present study employed a rodent model of high fructose-associated metabolic syndrome fed with high fructose diet (60%, HFD) for 12weeks. The levels of peripheral and central IR were assayed. Half of the HFD-fed rats received PIO gavage to investigate the levels of Iberiotoxin signaling, BDNF, adult neurogenesis in the hippocampus. Moreover, synaptic plasticity and gliosis were surveyed in the hippocampus. We hypothesize that PIO can at least partially protect HFD-impaired cognition through the anti-inflammation pathway.
Materials and methods
Discussion In this study, we evaluated the effects of oral PIO (30mg/kg/day, 2weeks) treatment on both peripheral and hippocampal IR induced by HFD. We found that oral application of PIO effectively reversed peripheral IR and was unable to reverse the hippocampal IR. In the hippocampus, HFD down-regulated BDNF, CaMKIIα, and PSD95. Concurrently, HFD activated microglia and astrocyte. On the other hand, inhibited hippocampal adult neurogenesis. PIO significantly reversed glial activation and the decrease of BDNF-associated postsynaptic events. On the other hand, PIO treatment did not rescue the inhibited adult neurogenesis and enhanced IR in the hippocampus. These results indicated that the uneven results of treatment in peripheral and hippocampal impairment may lead to underestimating the progression of HFD-induced cognitive dysfunction. Diet induces both peripheral and hippocampal IR. Insulin resistance is clearly correlated to hippocampal dysfunction . It is unclear that hippocampal IR is a result of hyperinsulinemia or occurred parallel to peripheral IR. An increase of autophosphorylation of IRS and the p85 subunit of PI3K with a decrease of phospho-Akt have been characterized as hippocampal IR . Similar to other studies , , , our data indicated that HFD for 12weeks triggered hippocampal IR at young adult rats. A growing body of human and animal research repurpose the diabetes drugs for brain IR . PPARs is a family of nuclear receptors that regulate the transcription of genes involved in lipid and glucose metabolism . PIO, a common insulin sensitizer, is a ligand for peroxisome proliferator-activated receptor γ (PPARγ) . However, PIO effects on cognitive improvement in human prospective studies are controversial , , . Our data indicated that PIO gavage for 2weeks effectively reversed the HFD-increased HOMA-IR and the down-regulation of PPARγ in the hippocampus. In contrast to the peripheral effect, PIO did not effectively reverse the molecular indexes of hippocampal IR. The evidence suggested that the PIO treatment in the present study was unable to reverse hippocampal IR. We reason that HFD may play a direct role in the development of hippocampal IR rather than indirectly through the HFD-induced hyperinsulinemia. Both our and the human prospective data may imply the difficulty to reverse the progression of hippocampal IR when it been initiated. With 18% blood-brain-barrier (BBB) permeability , it is conceivable that less PIO passed through BBB when compared with the circulating dose. Therefore, its capability to enhance insulin sensitivity can be limited. Based on the statistical analyses of one-way ANOVA, the hippocampal levels of p-IRS1, p85 subunit of PI3K, and p-Akt in the group with PIO treatment showed no significant differences in both normal diet or high fructose diet. Particularly, the statistical indifference between normal diet and the PIO-treated group could be a result of high variety ingroup. Our interpretation of these data is that enhancing PIO concentration in the hippocampus by increasing the dosage or extending the dosing period of PIO intake may improve the hippocampal IR. On the other hand, PIO has been proposed to activate both PPARα and PPARγ  for lipid and sugar metabolism, respectively. Whether PIO triggers the different signaling in hippocampus from peripheral pathways is waiting for further delineation.