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  • IR has been linked to the negative


    IR has been linked to the negative control of BDNF expression, a critical trophic factor in cognitive functions. The previous study indicated that 2month-old rats fed with a high-fat, high-sugar chow with water containing 20% high-fructose corn syrup for 8months showed an impairment of hippocampal synaptic plasticity and cognition in middle-aged rats [5]. In this study, we investigated the expression of hippocampal BDNF in young adult rat fed with HFD for 12weeks. In compared with the previous study [5], our data further indicated that high fructose consuming reduced the expression of hippocampal BDNF protein in a shorter intake period at a younger age. These pieces of evidence highlighted the hazard effect of HFD at a younger age. PIO effectively reversed the HFD-reduced BDNF. These results further implied that the mechanisms involved in hippocampal IR may be parallel to those in the BDNF reduction. It is, therefore, conceivable that reversed BDNF by PIO may only rescue hippocampal functions partially. By QPCR analyses, our study further indicated that the mRNAs of BDNF Z-Guggulsterone I, II, and IV were not significantly disturbed at each treatment. These results indicated that reduction of BDNF may be limited at the protein level, such as the low efficiency of translation or the high level of protein degradation. BDNF positively regulates hippocampal function in multiple ways, including the maintenance of synaptic plasticity and adult neurogenesis. CaMKII, a serine/threonine kinase with four isoforms (i.e. α, β, δ, and γ), is a major component of the postsynaptic density which are highly abundant in mammalian forebrain [50]. CaMKIIα plays important role in synaptic plasticity [51] under the control of BDNF [52]. In addition, BDNF has been documented to stabilize postsynaptic density of existing circuit by recruiting PSD-95 [53]. Long-term consumption of fructose impairs synaptic plasticity [5]. Concurrent with the decrease of BDNF, the Western blotting results further indicated that the expressions of CaMKIIα and PSD-95 in the hippocampus was reduced by 12-weeks HFD intake and was rescued by oral PIO treatment. On the other hand, the expression of synaptophysin, a key element of synaptic plasticity located in the presynaptic area, showed no significant difference between treatments. These are consistent with the results reported by Cisternas et al. ([54]) in mice. Taken together, these pieces of evidence highlighted the postsynaptic impairment of the pre-existed neuronal circuit in the hippocampus by HFD. Moreover, the study extended the finding by pointing out new target molecules in the hippocampus for PIO therapy. But due to the limitation of present study design, the underlying mechanisms of the selective inhibition by HFD at the postsynaptic area is currently unclear. The previous study reported that short-term fructose drinking altered hippocampal signaling accompanied by glial activation in rat [16]. Insulin resistance has been connected to the glial activation in the human study [55] while glia-derived proinflammatory cytokine is linked to the decrease of BDNF [56] at gene [27] and protein [26] levels. Consistently, our study indicated that HFD ingestion increased microglia and astrocyte activation concurrent with IR and BDNF reduction in the hippocampus. PIO administration restored BDNF level and attenuated inflammatory mediators in a rodent model of Alzheimer's disease, which is strongly linked to hippocampal IR [57]. Our study indicated that elimination of glial activation and upregulation of BDNF by PIO. Together, these pieces of evidence implied the interaction between HFD-induced neuroinflammation and BDNF reduction. Although neuroinflammation has been linked to the promotion of brain IR [58], our study indicated that PIO relieved microglia activation without mitigating hippocampal IR. Therefore, the linkage between glial activation and hippocampal IR in this model requires for further delineation. In the brain, PPARγ mainly distributes in the microglia and astrocyte and inhibits the expression of proinflammatory cytokines [59]. Oral application of PIO mitigated HFD-induced microglia and astrocyte activation which is consistent with previous study [55]. These pieces of evidence further linked the HFD-suppressed PPARγ to the activation of astrocyte and microglia in the hippocampus.