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Publication
Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK
activation and obesity-associated pathophysiology.
Authors Zhang C, Seo J, Murakami K, Salem ESB, Bernhard E, Borra VJ, Choi K, Yuan CL,
Chan CC, Chen X, Huang T, Weirauch MT, Divanovic S, Qi NR, Thomas HE, Mercer CA,
Siomi H, Nakamura T
Submitted By Submitted Externally on 4/30/2020
Status Published
Journal Nature communications
Year 2018
Date Published 9/1/2018
Volume : Pages 9 : 3658
PubMed Reference 30201950
Abstract RNA silencing inhibits 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 regulates both intrinsic energy production and
consumption and disturbs energy metabolism in the pathogenesis of obesity. Ago2
regulates expression of specific miRNAs including miR-802, miR-103/107, and
miR-148a/152, causing metabolic disruption, while simultaneously suppressing the
expression of genes regulating glucose and lipid metabolism, including Hnf1ß,
Cav1, and Ampka1. Liver-specific Ago2-deletion enhances mitochondrial oxidation
and ATP consumption associated with mRNA translation, which results in AMPK
activation, and improves obesity-associated pathophysiology. Notably, hepatic
Ago2-deficiency improves glucose metabolism in conditions of insulin receptor
antagonist treatment, high-fat diet challenge, and hepatic AMPKa1-deletion. 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.




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