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

Cai Zhang,Matthew T Weirauch,Joonbae Seo,Kazutoshi Murakami,Senad Divanovic,Vishnupriya J Borra,Taosheng Huang,Esam S B Salem,Elise Bernhard,Nathan R Qi,Calvin C Chan,Celvie L Yuan,Haruhiko Siomi,Carol A Mercer,Hala Einakat Thomas,Takahisa Nakamura,Xiaoting Chen,Kwangmin Choi

doi:10.1038/s41467-018-05870-6

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.

Highlights

If RNA silencing plays a role in protein biosynthesis-associated energy metabolism, one would anticipate that individual component(s) of miRNA-regulatory machinery in the liver may impinge on metabolic regulation, and that a nutrient challenge might accentuate the consequences of this regulation
To study the role of RNA silencing in hepatic energy homeostasis, we comprehensively evaluated the role of hepatic Ago[1] and Ago[2], as analyses of these core RNA-induced silencing complex (RISC) components might lead to fundamental insights into the link of RNA silencing with energy metabolism
The role of RNA silencing in suppressing mRNA translation gives rise to the intriguing hypothesis that the RNA silencing machinery might be tightly integrated with the regulation of basal metabolic activity and energy homeostasis, as mRNA translation requires a massive amount of energy

Summary

Introduction

The regulation of energy metabolism by Ago[2] provides a novel paradigm in which RNA silencing plays an integral role in determining basal metabolic activity in obesity-associated sequelae. Suppression of hepatic protein synthesis leads to further accumulation of energy sources associated with obesityassociated pathophysiology, the exact mechanism(s) of insufficient protein biosynthesis remains unclear Defining such molecular mechanism(s) could provide a novel therapeutic approach that alters energy balance in obesity and modulates the pathogenesis of associated sequelae. As miRNA generally inhibits the translation of target mRNAs through RNA silencing, it is reasonable to hypothesize that these induced miRNAs may contribute to suppression of protein biosynthesis and its associated energy expenditure in obese liver. If RNA silencing plays a role in protein biosynthesis-associated energy metabolism, one would anticipate that individual component(s) of miRNA-regulatory machinery in the liver may impinge on metabolic regulation, and that a nutrient challenge might accentuate the consequences of this regulation

Methods

Results

Conclusion