Argonaute2 Mediates Compensatory Expansion of the Pancreatic β Cell.

Sudhir G Tattikota, Thomas Rathjen, Sarah J McAnulty, Hans-Hermann Wessels, Ildem Akerman, Martijn van de Bunt, Jean Hausser, Jonathan Esguerra, Anne Musahl, Amit K Pandey, Xintian You, Wei Chen, Pedro L Herrera, Paul R Johnson, Donal O'Carroll, Lena Eliasson, Mihaela Zavolan, Anna L Gloyn, Jorge Ferrer, Ruby Shalom-FeuersteinDaniel Aberdam, Matthew N Poy

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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.
Original languageEnglish
Pages (from-to)122-134
JournalCell Metabolism
Volume19
Issue number1
DOIs
Publication statusPublished - 2014

Subject classification (UKÄ)

  • Cell and Molecular Biology

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