title: Argonaute2 mediates compensatory expansion of the pancreatic β cell.
abstract: Pancreatic β cells adapt to compensate for increased metabolic demand during insulin resistance. Although the microRNA pathway has an essential role in β cell proliferation, the extent of its contribution is unclear. Here, we report that miR-184 is silenced in the pancreatic islets of insulin-resistant mouse models and type 2 diabetic human subjects. Reduction of miR-184 promotes the expression of its target Argonaute2 (Ago2), a component of the microRNA-induced silencing complex. Moreover, restoration of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory β cell expansion. Loss of Ago2 during insulin resistance blocked β cell growth and relieved the regulation of miR-375-targeted genes, including the growth suppressor Cadm1. Lastly, administration of a ketogenic diet to ob/ob mice rescued insulin sensitivity and miR-184 expression and restored Ago2 and β cell mass. This study identifies the targeting of Ago2 by miR-184 as an essential component of the compensatory response to regulate proliferation according to insulin sensitivity.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Sudhir G
authors.initials: SG
authors.lastname: Tattikota
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rathjen
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: McAnulty
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Wessels
authors.affiliation: Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Ildem
authors.initials: I
authors.lastname: Akerman
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, OX3 7LE Oxford, UK.
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Hausser
authors.affiliation: Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.
authors.forename: Jonathan L S
authors.initials: JL
authors.lastname: Esguerra
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Musahl
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Pandey
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Xintian
authors.initials: X
authors.lastname: You
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, OX3 7LE Oxford, UK; NIHR Oxford Biomedical Research Centre, ORH Trust, OCDEM, Churchill Hospital, OX3 7LJ Oxford, UK; Nuffield Department of Surgery, University of Oxford, OX3 9DU Oxford, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Johnson
authors.affiliation: European Molecular Biology Laboratory, 00015 Monterotondo Scalo, Italy.
authors.forename: Donal
authors.initials: D
authors.lastname: O'Carroll
authors.affiliation: Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Zavolan
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, OX3 7LE Oxford, UK; NIHR Oxford Biomedical Research Centre, ORH Trust, OCDEM, Churchill Hospital, OX3 7LJ Oxford, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.affiliation: Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain; Department of Medicine, Imperial College London, W12 0NN London, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: Department of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, 31096 Haifa, Israel.
authors.forename: Ruby
authors.initials: R
authors.lastname: Shalom-Feuerstein
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 976, 75475 Paris, France; Université Paris Diderot, Skin Research Center, 75013 Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aberdam
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: matthew.poy@mdc-berlin.de.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Poy
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D055423:Diet, Ketogenic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism
chemical_list: C466422:AGO2 protein, human; C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; C534424:MIRN184 microRNA, human; C552233:MIRN184 microRNA, mouse; D035683:MicroRNAs; C540349:Mirn375 microRNA, mouse