Accumulated evidence indicates that
neuroinflammation induces
insulin resistance in the brain. Moreover, both processes are intimately linked to
neurodegenerative disorders, including
Alzheimer's disease. Potential mechanisms underlying
insulin resistance include
serine phosphorylation of the
insulin receptor substrate (IRS) or
insulin receptor (IR) misallocation. However, only a few studies have focused on IRS expression in the brain and its modulation in neuroinflammatory processes. This study used the high-fat diet (HFD) model of
neuroinflammation to study the alterations of IR, an
insulin-like growth factor receptor (IGF1R) and IRS expressions in the hippocampus. We observed that HFD effectively reduced
mRNA and
protein IRS2 expression. In contrast, a HFD induced the upregulation of the IRS1
mRNA levels, but did not alter an IR and IGF1R expression. As expected, we observed that a HFD increased hippocampal
tumor necrosis factor alpha (TNFα) and
amyloid precursor
protein (APP) levels while reducing
brain-derived neurotrophic factor (
BDNF) expression and neurogenesis. Interestingly, we found that TNFα correlated positively with IRS1 and negatively with IRS2, whereas APP levels correlated positively only with IRS1 but not IRS2. These results indicate that IRS1 and IRS2 hippocampal expression can be affected differently by HFD-induced
neuroinflammation. In addition, we aimed to establish whether
abscisic acid (ABA) can rescue hippocampal IRS1 and IRS2 expression, as we had previously shown that ABA supplementation prevents memory impairments and improves
neuroinflammation induced by a HFD. In this study, ABA restored HFD-induced hippocampal alterations, including IRS1 and IRS2 expression, TNFα, APP, and
BDNF levels and neurogenesis. In conclusion, this study highlights different regulations of hippocampal IRS1 and IRS2 expression using a HFD, indicating the important differences of these scaffolding
proteins, and strongly supports ABA
therapeutic effects.