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

Cai Zhang, Joonbae Seo, Kazutoshi Murakami, Esam S. B. Salem, Elise Bernhard, Vishnupriya J. Borra, Kwangmin Choi, Celvie L. Yuan, Calvin C. Chan, Xiaoting Chen, Taosheng Huang, Matthew T. Weirauch, Senad Divanovic, Nathan R. Qi, Hala Einakat Thomas, Carol A. Mercer, Haruhiko Siomi and Takahisa Nakamura ()
Additional contact information
Cai Zhang: Cincinnati Children’s Hospital Medical Center
Joonbae Seo: Cincinnati Children’s Hospital Medical Center
Kazutoshi Murakami: Cincinnati Children’s Hospital Medical Center
Esam S. B. Salem: Cincinnati Children’s Hospital Medical Center
Elise Bernhard: Cincinnati Children’s Hospital Medical Center
Vishnupriya J. Borra: Cincinnati Children’s Hospital Medical Center
Kwangmin Choi: Cincinnati Children’s Hospital Medical Center
Celvie L. Yuan: Cincinnati Children’s Hospital Medical Center
Calvin C. Chan: Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine
Xiaoting Chen: Cincinnati Children’s Hospital Medical Center
Taosheng Huang: University of Cincinnati College of Medicine
Matthew T. Weirauch: Cincinnati Children’s Hospital Medical Center
Senad Divanovic: University of Cincinnati College of Medicine
Nathan R. Qi: University of Michigan Medical School
Hala Einakat Thomas: University of Cincinnati College of Medicine
Carol A. Mercer: University of Cincinnati College of Medicine
Haruhiko Siomi: Keio University School of Medicine
Takahisa Nakamura: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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 Hnf1β, 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 AMPKα1-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.

Date: 2018
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DOI: 10.1038/s41467-018-05870-6

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