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

6 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

Fingerprint

obesity
AMP-Activated Protein Kinases
metabolism
RNA Interference
Energy Metabolism
Protein Biosynthesis
Obesity
Chemical activation
activation
RNA
Liver
deletion
Messenger RNA
Insulin Antagonists
glucose
Glucose
lipid metabolism
energy
Insulin Receptor
High Fat Diet

ASJC Scopus subject areas

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

Cite this

Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology. / Zhang, Cai; Seo, Joonbae; Murakami, Kazutoshi; Salem, Esam S.B.; Bernhard, Elise; Borra, Vishnupriya J.; Choi, Kwangmin; Yuan, Celvie L.; Chan, Calvin C.; Chen, Xiaoting; Huang, Taosheng; Weirauch, Matthew T.; Divanovic, Senad; Qi, Nathan R.; Thomas, Hala Einakat; Mercer, Carol A.; Siomi, Haruhiko; Nakamura, Takahisa.

In: Nature Communications, Vol. 9, No. 1, 3658, 01.12.2018.

Research output: Contribution to journalArticle

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 2018, 'Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology', Nature Communications, vol. 9, no. 1, 3658. https://doi.org/10.1038/s41467-018-05870-6
Zhang, Cai ; Seo, Joonbae ; Murakami, Kazutoshi ; Salem, Esam S.B. ; Bernhard, Elise ; Borra, Vishnupriya J. ; Choi, Kwangmin ; Yuan, Celvie L. ; Chan, Calvin C. ; Chen, Xiaoting ; Huang, Taosheng ; Weirauch, Matthew T. ; Divanovic, Senad ; Qi, Nathan R. ; Thomas, Hala Einakat ; Mercer, Carol A. ; Siomi, Haruhiko ; Nakamura, Takahisa. / Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology. In: Nature Communications. 2018 ; Vol. 9, No. 1.
@article{38f40c35d7024f058c2d984d89b760b1,
title = "Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology",
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.",
author = "Cai Zhang and Joonbae Seo and Kazutoshi Murakami and Salem, {Esam S.B.} and Elise Bernhard and Borra, {Vishnupriya J.} and Kwangmin Choi and Yuan, {Celvie L.} and Chan, {Calvin C.} and Xiaoting Chen and Taosheng Huang and Weirauch, {Matthew T.} and Senad Divanovic and Qi, {Nathan R.} and Thomas, {Hala Einakat} and Mercer, {Carol A.} and Haruhiko Siomi and Takahisa Nakamura",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-05870-6",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85053182490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053182490&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-05870-6

DO - 10.1038/s41467-018-05870-6

M3 - Article

C2 - 30201950

AN - SCOPUS:85053182490

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3658

ER -