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, Takahisa Nakamura

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Article number3658
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Zhang, C., Seo, J., Murakami, K., Salem, E. S. B., Bernhard, E., Borra, V. J., Choi, K., Yuan, C. L., Chan, C. C., Chen, X., Huang, T., Weirauch, M. T., Divanovic, S., Qi, N. R., Thomas, H. E., Mercer, C. A., Siomi, H., & Nakamura, T. (2018). Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology. Nature communications, 9(1), [3658]. https://doi.org/10.1038/s41467-018-05870-6