Oral pioglitazone ameliorates fructose-induced peripheral insulin resistance and hippocampal gliosis but not restores inhibited hippocampal adult neurogenesis

Diet-associated insulin resistance (IR) is intimately correlated with the progression of metabolic syndrome and hippocampal dysfunction. Pioglitazone (PIO), a selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has been applied to enhance insulin sensitivity. With limited permeability to blood-brain-barrier, it is unclear that whether oral PIO available to cure both the peripheral IR and the impairment in the hippocampus. We evaluated the levels of peripheral and hippocampal IR via the homeostatic model assessment of insulin resistance and hippocampal IRS-1/Akt phosphorylation, respectively, of Wistar Kyoto rats fed with a regular chew or high fructose diet (HFD) for 12 weeks. Gavage with PIO (30 mg/kg/day, 2 weeks) significantly reduced the peripheral IR and reversed the level of hippocampal PPARγ. Moreover, HFD-activated microglia and astrocyte were effectively relieved by PIO. The suppressed brain-derived neurotrophic factor, CaMKIIα, and postsynaptic density protein 95 in the hippocampus were effectively reversed by PIO. However, the hippocampal IR and inhibition of adult neurogenesis in dentate gyrus were not restored by PIO. Together, PIO oral application may reverse the HFD-induced peripheral IR and maintain the existed neuronal circuit by ameliorating glial activation and enhancing synaptic density through BDNF but failed to restore adult neurogenesis in the hippocampus.