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

Abstract

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.

• Authors: J Song, S M Kang, E Kim, C-H Kim, H-T Song, J E Lee
• Journal: Neuroscience (Neuroscience) Vol. 301 Pg. 26-38 (Aug 20 2015) ISSN: 1873-7544 [Electronic] United States
• PMID: 26047734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Forkhead Box Protein O3
• Forkhead Transcription Factors
• FoxO3 protein, mouse
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Reactive Oxygen Species
• Oncogene Protein v-akt

Topics

• Animals
• Apoptosis
• Brain (metabolism, pathology)
• Cell Line, Tumor
• Diet, High-Fat
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Male
• Mice
• Mice, Inbred ICR
• Neurites (metabolism)
• Neurons (metabolism, pathology)
• Oncogene Protein v-akt (metabolism)
• Phosphorylation
• Reactive Oxygen Species
• Signal Transduction