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.
Highlights
The incidence of obesity is increasing worldwide, in part due to changes in nutritional habits and lifestyle
There was a decline in the percentage time spent in the target quadrant in high fat diet (HFD) rats compared with the control group (Fig 1D)
A pathogenic role for chronic endoplasmic reticulum stress (ERS) has been identified in neurodegenerative diseases that are characterized by excessive intracellular accumulation and aggregation of misfolded proteins, for example in Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS) [25,26,27]
Summary
The incidence of obesity is increasing worldwide, in part due to changes in nutritional habits and lifestyle. The central nervous system (CNS) is one of the systems affected by obesity. An increasing number of studies have focused on cognitive impairment induced by obesity, its underlying mechanisms remain unclear. Insulin receptors are expressed ubiquitously in the brain [7]. Circulating insulin can enter the brain by crossing the blood—brain barrier, where it can activate signaling pathways in the CNS. Metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus (T2DM), and Alzheimer’s disease (AD) are associated with insulin resistance within the CNS, which may result from genetic polymorphisms or long-term exposure to elevated levels of circulating insulin due to peripheral insulin resistance
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
