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Cincinnati Children’s Hospital Medical Center
Nat. Commun., Published 10 September 2018, 9, Article number: 3658 | https://doi.org/10.1038/s41467-018-05870-6
Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology
Cai Zhang1,2, Joonbae Seo1, Kazutoshi Murakami1, Esam S.B. Salem1,3, Elise Bernhard1, Vishnupriya J. Borra1, Kwangmin Choi4, Celvie L. Yuan1, Calvin C. Chan5, Xiaoting Chen6, Taosheng Huang7,8, Matthew T. Weirauch 6,7,9,10, Senad Divanovic7,11, Nathan R. Qi12, Hala Einakat Thomas13, Carol A. Mercer13, Haruhiko Siomi14 & Takahisa Nakamura1,7,9,*
1Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 2Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 3Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 4Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 5 Medical Scientist Training Program, Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA. 6Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 7Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 8Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 9Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 10 Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 11Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 12Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. 13Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 14Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan. These authors contributed equally: Cai Zhang, Joonbae Seo, Kazutoshi Murakami.
*Correspondence to Takahisa Nakamura
1Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 2Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 3Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 4Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 5 Medical Scientist Training Program, Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA. 6Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 7Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 8Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 9Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 10 Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 11Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 12Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. 13Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 14Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan. These authors contributed equally: Cai Zhang, Joonbae Seo, Kazutoshi Murakami.
*Correspondence to Takahisa Nakamura
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.
논문정보
- Research article
- 2018년 09월 (BRIC 등록일 2018-09-14)
- 국외 연구진
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