TY - JOUR
T1 - Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology
AU - Zhang, Cai
AU - Seo, Joonbae
AU - Murakami, Kazutoshi
AU - Salem, Esam S.B.
AU - Bernhard, Elise
AU - Borra, Vishnupriya J.
AU - Choi, Kwangmin
AU - Yuan, Celvie L.
AU - Chan, Calvin C.
AU - Chen, Xiaoting
AU - Huang, Taosheng
AU - Weirauch, Matthew T.
AU - Divanovic, Senad
AU - Qi, Nathan R.
AU - Thomas, Hala Einakat
AU - Mercer, Carol A.
AU - Siomi, Haruhiko
AU - Nakamura, Takahisa
N1 - Funding Information:
We thank Drs. James Wells, Harinder Singh, David A D’Alessio, and Vivian Hwa for their scientific input and discussion. We also thank Drs. Rebekah Karns, Taishi Kimura, and Kahori Ikeda for their bioinformatics and technical supports and Dr. Eric Lai for generously providing us Ago2-deficient fibroblasts. This work was supported by National Institute of Health (NIH) (R01DK107530). T.N. was supported by the PRESTO from the Japan Science and Technology Agency. A part of this study was supported by grants from NIH (R01DK099222) to S.D. and P30DK078392 for the Digestive Disease Research Core Center in Cincinnati.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-05870-6
DO - 10.1038/s41467-018-05870-6
M3 - Article
C2 - 30201950
AN - SCOPUS:85053182490
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3658
ER -
