Metabolic diseases appear as clusters including obesity, insulin resistance, type 2 diabetes, and cardiovascular disease, and constitute a major global health problem with limited treatment options. In the past decade, it has been realized that the emergence of this cluster has strong inflammatory underpinnings (Hotamisligil, 2006
). During the course of obesity, a broad array of inflammatory and stress responses are evoked in metabolic tissues, leading to chronic, low grade local inflammation which plays a central role in the inhibition of insulin receptor signaling and disruption of systemic metabolic homeostasis. This atypical state, which we refer to as metaflammation (Hotamisligil, 2006
), involves immune and non-immune cells and the engagement of immune response pathways with nutrients and metabolites. However, the mechanistic basis of these extensive functional links and molecules that coordinate this network of responses remains to be understood.
If the nutrient and pathogen response systems were truly integrated, the involvement of pathogen sensors in metabolic regulation, especially during exposure to excess nutrients would be anticipated. Such anticipation has stimulated the pursuit of pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) for a role in metabolism (Shi et al., 2006
). Other than PRRs, there are only a few molecules that can assume such a role to carry the potential ability for direct recognition of pathogens and possess catalytic activity to directly couple to metabolic pathways. One such molecule is the double-stranded RNA-dependent protein kinase (PKR), which has been originally identified as a pathogen sensor and a proposed regulator of the innate immune response against viral infections in higher eukaryotes (Samuel, 1993
). Virus-derived double-stranded RNA molecules are recognized and bound by PKR through the N-terminal double-stranded RNA-binding motifs, resulting in autophosphorylation through the activation of the intramolecular kinase domain (Garcia et al., 2006
; Williams, 2001
). Interestingly, in the context of infections, PKR can regulate or act in conjunction with major inflammatory signaling pathways that are implicated in metabolic homeostasis, including the c-Jun N-teminal kinase (JNK) and IκB kinase (IKK) (Bonnet et al., 2000
; Goh et al., 2000
; Takada et al., 2007
). In metabolic disease, it is unclear how these and other inflammatory signaling molecules are coordinately regulated to disrupt metabolism. However, it is feasible to consider a model where these multiple signaling pathways act in concert by forming a response node or acting in complexes that yield to metabolic surplus.
Interestingly, among the very few substrates identified for the kinase activity of PKR, the major one is the eukaryotic initiation factor 2α (eIF2α), which regulates general protein synthesis (Holcik and Sonenberg, 2005
; Ron and Walter, 2007
). It has been postulated that PKR-mediated phosphorylation of eIF2α is a strategy to inhibit viral protein synthesis in host cells (Holcik and Sonenberg, 2005
). However, in other context, inhibition of general translation through the same eIF2α phosphorylation represents a major arm controlling endoplasmic reticulum (ER) homeostasis (Ron and Walter, 2007
). ER stress also plays an important role in the development of insulin resistance and diabetes, at least in part, by triggering JNK activity (Gregor and Hotamisligil, 2007
; Ozcan et al., 2004
). In both mouse and human, there is consistent and marked increase in phosphorylation of eIF2α and JNK activity in obese metabolic tissues (Gregor et al., 2009
). Hence, coordination of protein synthesis through eIF2α and stress signaling through JNK likely represent a relevant mechanism in the integration of inflammatory signals with metabolic outcomes, especially in the context of nutrient and energy surplus. PKR features properties to coordinate pathogen responses, endoplasmic reticulum function, inflammatory signaling, and translational regulation. Hence, we postulate that PKR may represent a core component of a putative “metabolic inflammasome”. In other words, an integration mechanism for pathogen response and metabolic pathways that plays a critical role in obesity, insulin action, and type 2 diabetes by controlling the action of major players such as JNK, IKK and/or other mediators to regulate metabolic homeostasis.