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 L.S. 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 Poy

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)122-134
Number of pages13
JournalCell Metabolism
Volume19
Issue number1
DOIs
StatePublished - Jan 7 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Tattikota, S. G., Rathjen, T., McAnulty, S. J., Wessels, H. H., Akerman, I., Van De Bunt, M., Hausser, J., Esguerra, J. L. S., Musahl, A., Pandey, A. K., You, X., Chen, W., Herrera, P. L., Johnson, P. R., O'Carroll, D., Eliasson, L., Zavolan, M., Gloyn, A. L., Ferrer, J., ... Poy, M. (2014). Argonaute2 mediates compensatory expansion of the pancreatic β cell. Cell Metabolism, 19(1), 122-134. https://doi.org/10.1016/j.cmet.2013.11.015