Impairment of insulin receptor substrate 1 signaling by insulin resistance inhibits neurite outgrowth and aggravates neuronal cell death

•High-fat diet contributes to insulin resistance through IRS-1/Akt signaling.•The impairment of the IRS-1/Akt under insulin resistance aggravates apoptosis.•Impairment of the IRS-1 signaling results in the inhibition of neurite outgrowth.

In the central nervous system (CNS), insulin resistance (I/R) can cause defective neurite outgrowth and neuronal cell death, which can eventually lead to cognitive deficits. Recent research has focused on the relationship between I/R and the cognitive impairment caused by dementia, with the goal of developing treatments for dementia. Insulin signal transduction mediated by insulin receptor substrate (IRS-1) has been thoroughly studied in the CNS of patients with I/R. In the present study, we investigated whether the impairment of IRS-1-mediated insulin signaling contributes to neurite outgrowth and neuronal loss, both in mice fed a high-fat diet and in mouse neuroblastoma (Neuro2A) cells. To investigate the changes caused by the inhibition of IRS-1-mediated insulin signaling in the brain, we performed Cresyl Violet staining and immunochemical analysis. To investigate the changes caused by the inhibition of IRS-1-mediated insulin signaling in neuroblastoma cells, we performed Western blot analysis, reverse transcription-PCR, and immunochemical analysis. We show that the deactivation of IRS-1-mediated insulin signaling can inhibit neuronal outgrowth and aggravate neuronal cell death in the insulin-resistant CNS. Thus, IRS-1-mediated insulin signal transduction may be an important factor in the treatment of cognitive decline induced by I/R.