Adult neurogenesis is a process to generate newborn
Adult neurogenesis is a process to generate newborn neuron which could integrate into existing circuits to maintain cognitive functions. Several critical stages are involved, including neural progenitor cell proliferation, differentiation, survival, migration and neurite outgrowth . BDNF promotes adult neurogenesis in the hippocampus  while overnutrition suppressed this process . We found that the numbers of neural progenitor cell proliferation, neural differentiation and survived new-born neuron were significantly suppressed by HFD ingestion. These pieces of evidence have consisted with previous study feeding 2-month-old mice with 20% drinking fructose for 7weeks . Together, these pieces of evidence further emphasize the vulnerable of adult neurogenesis under sub-chronic HFD intake which may result in less capacity to maintain the pre-existed neural network. Although the decrement of hippocampal BDNF coexisted with the suppression of adult neurogenesis, the impaired adult neurogenesis was not reversed when the BDNF level raised by PIO treatment. We reason that adult neurogenesis was damaged at an earlier stage of HFD ingestion and was unable to be rescued by PIO at later stage making the existed neuronal network much more vulnerable than the ND group. Furthermore, increased proinflammatory cytokines negatively affect neurogenesis. For example, blockade of interleukin 1β (IL-1β) signaling prevents the decrease of neurogenesis . IL-6 suppresses neurogenesis in favor of astrogenesis , . Tumor necrosis factor α (TNF-α) negative regulates neurogenesis by reducing neural stem cell proliferation . These lines of evidence further connected both the BDNF reduction and the glial activation to the suppression of adult neurogenesis.
In the hippocampus, the Fluxametamide of PPARγ locates mainly in the dentate gyrus . The role of PPARγ in proliferation and differentiation of murine neural stem cell is controversial. Some reports suggest that PPARγ results in the inhibition of neuronal differentiation ,  while the other documents suggest that it positively regulates cell proliferation and differentiation in the brain , . We found that ND animal with PIO treatment resulted in decreases of cell proliferation, neuronal differentiation and new-born neuron survival (data not shown). Although PIO worked for BDNF enhancement, it is conceivable that the negative effect of PIO on neurogenesis may result in the irreversed inhibition of adult neurogenesis observed in the present study. In addition, brain IR impairs adult neurogenesis in the dentate gyrus , . These lines of evidence in the present study implied the linkage between hippocampal IR and the decrease of adult neurogenesis. Whether the suppression of adult neurogenesis resulting from the impairment of insulin signaling in neural stem cell requires for further delineation. Of note, the cure of peripheral metabolic indexes may not necessary means the cure of hippocampal dysfunction impaired by HFD. Thus, the dosage, duration, and path of PIO treatment to enhance the adult neurogenesis in dentate gyrus insulted under metabolic syndrome requires for further delineation.
Conclusion Together, our study indicated that health WKY rat with 12weeks HFD ingestion developed both peripheral and hippocampal IR. PIO treatment perfectively rescued the HFD-induced peripheral IR, hypertriglyceridemia, and hypertension. In the hippocampus, the glial activation and the reduction of BDNF, CaMKIIα, and PSD-95 were effectively reversed to the basal levels by PIO. On the other hand, the hippocampal IR and the suppression of adult neurogenesis in dentate gyrus were not mitigated by oral application with PIO. The following is the Supplementary data related to this article.
Formatting of funding sources This study was supported in part by research grants VGHKS104-039 to WCL from Kaohsiung Veterans General Hospital, CMRPG8E0701 to MHF from the Chang Gung Memorial Hospital and CMRPG8D0101, CMPRG8F0061 to KLHW from the Chang Gung Memorial Hospital, Taiwan, Republic of China.