Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology. Mus musculus

RNA silencing is an inhibitory process of mRNA translation. While mRNA translation accounts for the majority of cellular energy expenditure, it is unclear if RNA silencing regulates energy homeostasis. Here, we report that hepatic Argonaute 2 (Ago2)-mediated RNA silencing intrinsically functions to suppress both energy production and consumption, thereby disturbing a flow of cellular energy and activation of AMP-activated protein kinase (AMPK) in the pathogenesis of obesity. Ago2 selectively induces miRNAs known to cause metabolic disruption, including miR-802, miR-103/107, and miR-148a/152, while simultaneously suppressing expression of genes that improve mitochondrial functions, most notably AMPKa1, for which Ago2’s slicer activity is crucial. Liver-specific deletion of Ago2 enhances mitochondrial functions and also ATP consumption associated with mRNA translation, which results in AMPK activation and improves obesity-associated pathophysiology. These data indicate that hepatic Ago2 is an essential enzymatic switch that controls AMPK expression and activation and is a therapeutic target for metabolic diseases. The regulation of energy metabolism by Ago2 provides a novel paradigm in which RNA silencing plays an integral role in determining basal metabolic activity in obesity-associated sequelae