Roles of Hepatic miRNA Regulatory Machinery in Obesity

Alterations in microRNA (miRNA) expression associated with obesity can induce disruption of metabolic homeostasis, leading to metabolic diseases such as type 2 diabetes (T2D). However, the mechanisms by which the miRNA-regulatory machinery participates in the pathogenesis of obesity remain unknown.

We previously reported 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 metabolic dysregulation. Recently, we further demonstrated that PKR forms a unique protein complex with components of RNA-induced silencing complex (RISC) and RISC-loading complex (RLC) in the obese liver. More importantly, inactivation of key components of RISC or RLC in the obese liver results in reversal of glucose intolerance and hepatic steatosis, accompanied by a drastic change in the miRNA expression profile and reduced activation of PKR. These findings indicate that hepatic miRNA-regulatory machinery plays a crucial role in the development of abnormal glucose and lipid metabolism in obesity. Our new study has revealed that the biogenesis of hepatic miRNAs known to induce T2D is selectively regulated by a specific component of RISC in the pathogenesis of obesity. These results have significant implications for understanding the role of hepatic miRNA and its regulatory machinery in the regulation of metabolic homeostasis and for defining an entirely novel class of therapeutics for metabolic diseases.