title: Endoplasmic reticulum stress impairs insulin receptor signaling in the brains of obese rats.
abstract: The incidence of obesity is increasing worldwide. It was reported that endoplasmic reticulum stress (ERS) could inhibit insulin receptor signaling by activating c-Jun N-terminal kinase (JNK) in the liver. However, the relationship between ERS and insulin receptor signaling in the brain during obesity remains unclear. The aim of the current study was to assess whether ERS alters insulin receptor signaling through the hyper-activation of JNK in the hippocampus and frontal cortex in the brains of obese rats. Obesity was induced using a high fat diet (HFD). The Morris water maze test was then performed to evaluate decreases in cognitive function, and western blot was used to verify whether abnormal insulin receptor signaling was induced by ERS in HFD rats exhibiting cognitive decline. In addition, to determine whether ERS activated JNK and consequently impaired insulin receptor signaling, SH-SY5Y cells were treated with the JNK inhibitor, SP600125, followed by tunicamycin or thapsigargin, and primary rat hippocampal and cortical neurons were transfected with siRNA against IRE1α and JNK. We found that the expression of phosphorylation of PKR-like kinase (PERK), phosphorylation of α subunit of translation initiation factor 2 (eIF2α), and phosphorylation of inositol-requiring kinase-1α (IRE-1α) were increased in the brains of rats with HFD when compared with control rats. The level of serine phosphorylation of insulin receptor substrate-1 (IRS-1) was also increased, while protein kinase B (PKB/Akt) was reduced. ERS was also found to inhibit insulin receptor signaling via the activation of JNK in SH-SY5Y cells, primary rat hippocampal, and cortical neurons. These results indicate that ERS was increased, thereby resulting in impaired insulin receptor signaling in the hippocampus and frontal cortex of obese rats.
authors.affiliation: College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Liang
authors.affiliation: College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Traditional Chinese Medicine, the Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China; College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Zhan
authors.affiliation: Department of Emergency Medicine, Zhongshan Hospital, Dalian University, Dalian, Liaoning, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Lu
authors.affiliation: College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Sun
authors.affiliation: College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Sui
authors.affiliation: College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Luping
authors.initials: L
authors.lastname: Zheng
authors.affiliation: College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.affiliation: Institute of Public Hygiene, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Fuliang
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D011972:Receptor, Insulin