title: 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.affiliation: Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, South Korea. Electronic address: sjh1008@yuhs.ac.
authors.forename: J
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, South Korea; BK21 Plus Project for Medical Sciences and Brain Research Institute, Yonsei University College of Medicine, Seoul 120-752, South Korea. Electronic address: somangkang@yuhs.ac.
authors.forename: S M
authors.initials: SM
authors.lastname: Kang
authors.affiliation: Department of Psychiatry, Yonsei University College of Medicine, Seoul 120-752, South Korea. Electronic address: KIMEOSU@yuhs.ac.
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul 120-752, South Korea. Electronic address: KIMHOON@yuhs.ac.
authors.forename: C-H
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Diagnostic Radiology, Yonsei University College of Medicine, Seoul 120-752, South Korea. Electronic address: HOTSONG@yuhs.ac.
authors.forename: H-T
authors.initials: HT
authors.lastname: Song
authors.affiliation: Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, South Korea; BK21 Plus Project for Medical Sciences and Brain Research Institute, Yonsei University College of Medicine, Seoul 120-752, South Korea. Electronic address: jelee@yuhs.ac.
authors.forename: J E
authors.initials: JE
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D059305:Diet, High-Fat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D015398:Signal Transduction
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D017382:Reactive Oxygen Species; D051058:Oncogene Protein v-akt
keywords: high-fat diet (HFD) animal model; insulin receptor substrate 1 (IRS-1); insulin resistance; neurite outgrowth; neuronal cell death