The worldwide prevalence of obesity has reached pandemic proportions, and with it have come other associated metabolic diseases, such as insulin resistance and type 2 diabetes (T2D). Intensive research has identified the frequent coexistence of obesity with a state of inflammation in metabolic tissues such as adipose tissue and liver [1]. Multiple inflammatory and stress responses are evoked in these metabolic tissues, leading to chronic, low grade, local inflammation that plays a central role in the disruption of systemic metabolic homeostasis during the pathogenesis of obesity. This atypical state engages immune response pathways, including recruitment of immune cells into metabolic tissues, activation of IB kinase (IKK) and c-Jun N-terminal kinase (JNK) pathways, and elevated production of an array of immune mediators that impact nutrient metabolism and insulin action [1]. However, the molecular basis for the induction of metabolic inflammation and the vast network of pathological responses remains to be elucidated. In general, a majority of cellular double-stranded RNA (dsRNA)-binding proteins, such as dsRNA-dependent protein kinase (PKR) and retinoic acidinducible gene-I (RIG-I)-like receptor family, have been known to exclusively recognize exogenous dsRNA and induce inflammatory responses [2]. However, recent evidence has clearly shown that a variety of endogenous dsRNA exist and are involved in multiple cellular events including RNA silencing, which requires stringent regulation of dsRNA-to-dsRNA-binding protein interactions. As many dsRNA-binding proteins are intrinsically pro-inflammatory, regulatory disruption in endogenous dsRNA-protein networks may also cause inflammatory responses. We have hypothesized that such a disruption occurs in obesity, resulting in inflammation, insulin resistance, and metabolic dysfunction. This hypothesis has allowed us to identify PKR as a negative regulator of insulin action and glucose metabolism in obesity [3].

PKR, a pathogen-sensing protein, is activated by excess nutrients and its aberrant activity plays a key role in the induction of inflammatory responses, insulin resistance, and abnormal glucose metabolism in obesity [3]. In addition, exposure of cells and tissues to lipotoxicity leads to PKR activation, PKR-dependent activation of JNK, and phosphorylation of eukaryotic initiation factor 2α (eIF2α), a direct substrate of PKR [3]. Importantly, PKR and JNK activities as well as eIF2α phosphorylation are elevated in multiple tissues in obese