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.

Alleviating VLDL overproduction is an important mechanism for Laminaria japonica polysaccharide to inhibit atherosclerosis in LDLr−/− mice with diet‐induced insulin resistance

“…6G). Liang et al reported that HFD increased the phosphorylation of IRS-2 Ser 731 in the hippocampus of rats, leading to IR [40]. In the present work, we also found HFD enhanced the phosphorylated levels of ISR2, which was suppressed by LJP61A in vivo and in vitro ( Fig.…”

The signaling mechanisms of hippocampal endoplasmic reticulum stress affecting neuronal plasticity-related protein levels in high fat diet-induced obese rats and the regulation of aerobic exercise

“…Moderate ERS serves as a protective mechanism through activating unfolded protein response (UPR), but prolonged or excessive ERS can induce apoptosis (Tabas and Ron, 2011). Some animal studies have shown that HFD-induced obesity could cause hypothalamic ERS, which is linked to leptin/insulin resistance and diminished cognitive function (Liang et al, 2015;Won et al, 2009).…”

Impaired insulin signaling and spatial learning in middle-aged rats: The role of PTP1B

“…It is already known that the downregulation of IR specifically in the hippocampus resulted in deficits in the synaptic transmission associated with impairments in the spatial learning (Grillo et al, 2015). Several studies investigating insulin resistance/insufficiency described similar spatial learning deficits in diabetic (Diegues et al, 2014), obese (Liang et al, 2015) and aged (Gallagher et al, 2015) animals. An interesting study reviewed several transgenic AD models with a focus on performance in MWM and other behavioral assays (Puzzo et al, 2014).…”