The role of PKR in the interaction between gut microbiota and intestinal barrier on host's metabolic responses

Abstract

Double-stranded RNA-dependent protein kinase (PKR) represents a core component that integrates pathogen response and metabolic pathways that plays a critical role in metabolic homeostasis by controlling the action of major players such as JNK and IKK. In obese mice, PKR activation is associated with insulin signaling impairment and glucose intolerance. However PKR's ligands are still unknown. It is possible that lipids that come from the diet may activate PKR and inflammasome directly, but also gut microbiota-derived components may have a role as ligands for this known pathogen sensor in obese individuals, since obesity and its metabolic alterations have been associated with changes in the composition of the gut microbiota. These bacterial changes are correlated with increased lipopolysaccharide (LPS) absorption in high-fat diet feeding due to increased intestinal permeability, leading to increased expression of inflammatory markers. However, the mechanisms by which impairment in the gut barrier is developed during obesity are poorly understood. PKR, as a sensor of pathogens and nutrients, couples information about the local nutrient or metabolite environment to coordinate immune responses. Therefore, studying PKR in a interface where it can recognize both components of the gut microbiota and nutrients is a unique opportunity to integrate immune responses and metabolism, which will contribute for the comprehension of molecular mechanisms leading to inflammation and insulin resistance in obesity, with great potential in the search for new drug targets to treat obesity and associated diseases. (AU)