Role of protein kinase R in metabolic homeostasis
Creators: name: Pindel, Agnieszka
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: Obesity related conditions, predominantly cardiovascular disease and diabetes constitute the most significant burden to healthcare in much of the western world. The physiological response to excess nutrients influences the health consequence of obesity. Hence regulation of cellular processes that maintain energy homeostasis, such as protein translation, are critical to the pathogenesis of metabolic disease. The Protein Kinase R (PKR) participates in cell signalling and plays a key role in the maintenance of protein translation by regulating the activity of the eukaryotic initiation factor 2-alpha (eIF2α). We hypothesized that metabolic sensing via PKR and its substrate, eIF2α, would initiate a general stress response to high fat diets that then modulates obesity-related diseases. This study provides the first evidence supportive of a critical role for PKR in regulating metabolic and inflammatory responses to ameliorate diet-induced obesity and ensuing pathologies. PKR ameliorates weight gain and subcutaneous fat mass deposition in response to a high fat diet. However, the detected decrease in locomotor activity and BAT temperature in mice ablated for PKR was found to not be statistically significant. Loss of PKR also perturbs major lipid signalling pathways, resulting in augmented expression of fatty acid synthase (FASN) and diacylglycerol transferase 2 (DGAT2), both of which induce triglyceride synthesis and likely contribute to adipose tissue expansion. Indeed, mice ablated for PKR are hyperlipidemic as reflected by increased serum concentration of triglycerides, decreased concentration of low-density lipoprotein (LDL) and an unfavourable ration of high to low density lipoprotein (HDL/LDL). The consequence of this altered lipid metabolism is explored by measuring the effect of PKR deficiency on obesity associated cardiovascular disease in the apolipoprotein E (apoE) deficient mouse as a model for atherosclerosis. Ablating PKR from mice also deficient in apoE exacerbates diet-induced atherosclerosis, confirming that PKR plays a key role in disease development. We also show that PKR maintains pancreatic islet size and normal glucose homeostasis. Ablation of PKR increases expression of the gluconeogenic enzyme glucose-6-phosphatase (G6pase) in the liver accounting for increased hepatic glucose production and glucose intolerance. We also establish that PKR deficiency in vitro suppresses expression of the insulin receptor substrate 2 (IRS2) and consequently disrupts insulin signalling by reducing phosphorylation of p70S6K. In contrast to a recent report by Nakamura et al, that PKR promotes diet-induced obesity by increasing inflammation and suppressing insulin signalling by phosphorylation of IRS1, we see no PKR-dependent regulation of classic inflammatory cytokines IL-6 and TNF-α. Instead, in the absence of PKR heightens secretion of IL-1β from the pancreas, which has previously been reported to associate with pancreatic islet cell damage and disturbed glucose homeostasis. The mechanism likely to explain this effect is PKR-mediated inflammasome activation; however further research is required to confirm this mode of action. Collectively these findings demonstrate that PKR is protective against diet-induced weight gain and the pathogenesis of metabolic disease. These results fit in with the principle function of PKR to relieve stress by inducing the integrated stress response.