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【演題・演者】
Role of dsRNA-mediated immunometabolic regulation in obesity

Takahisa Nakamura, Ph.D.

Divisions of Endocrinology and Developmental Biology

Cincinnati Children’s Hospital Medical Center

With the rise of obesity, the prevalence of metabolic diseases, such as insulin resistance and type 2 diabetes, has increased to pandemic proportions. Intensive research has identified the coexistence of obesity with a state of chronic inflammation in which excess nutrients trigger inflammatory and stress responses, involving recruitment of immune cells, elevated production of immune mediators, and activation of stress kinase pathways. These anomalous inflammatory and stress responses are key in the pathogenesis of obesity-induced metabolic dysfunction.

We have recently discovered that double-stranded RNA (dsRNA)-dependent kinase (PKR), a pathogen-sensing stress kinase, is activated in the liver by excess nutrients and that its aberrant activities play key roles in obesity-induced inflammation and insulin resistance. More recently, we have demonstrated that PKR forms a unique protein complex with trans-activation response-RNA binding protein (TRBP), a major component of RNA-induced silencing complex (RISC)-loading complex (RLC), under metabolic stress conditions. TRBP has at least two molecular functions: 1) microRNA (miRNA) biogenesis as a component of RLC and 2) regulating inflammatory responses by modifying PKR activity. We showed that inactivation of TRBP in obese liver affects both of these processes, resulting in reversal of hepatic steatosis and glucose intolerance, accompanied by an altered miRNA expression profile and reduced activation of PKR and c-Jun N-terminal kinase (JNK). Of note, we have also observed that TRBP is highly phosphorylated in obese liver. This leads to the promotion of miRNA biogenesis and activation of PKR, which are associated with the pathogenesis of glucose intolerance. These data indicate that the association between PKR and TRBP integrates metabolism with inflammatory signaling and miRNA biogenesis and plays important roles in metabolic homeostasis and disease in obesity.