Argonaute2 Mediates Compensatory Expansion of the Pancreatic β Cell

• Published in: Cell metabolism Vol. 19; no. 1; pp. 122 - 134
• Main Authors: Tattikota, Sudhir G., Rathjen, Thomas, McAnulty, Sarah J., Wessels, Hans-Hermann, Akerman, Ildem, van de Bunt, Martijn, Hausser, Jean, Esguerra, Jonathan L.S., Musahl, Anne, Pandey, Amit K., You, Xintian, Chen, Wei, Herrera, Pedro L., Johnson, Paul R., O’Carroll, Donal, Eliasson, Lena, Zavolan, Mihaela, Gloyn, Anna L., Ferrer, Jorge, Shalom-Feuerstein, Ruby, Aberdam, Daniel, Poy, Matthew N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-01-2014; Cell Press
• Subjects: Animals; Argonaute Proteins - metabolism; Basic Medicine; Cell and Molecular Biology; Cell Proliferation; Cell- och molekylärbiologi; Diet, Ketogenic; Gene Expression Regulation; Gene Silencing; Humans; Insulin Resistance - genetics; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Obese; MicroRNAs - genetics; MicroRNAs - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2013.11.015

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.
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•Silencing of miR-184 during insulin resistance promotes its target Ago2•Loss of Ago2 during insulin resistance blocks pancreatic β cell proliferation•Ago2 mediates the suppression of Cadm1 by miR-375 in the β cell•Administration of the ketogenic diet to ob/ob mice rescues miR-184 in islets
Tattikota et al. find that as β cells adapt to increased metabolic demand during insulin resistance in obesity, miR-184 is silenced to alleviate repression of its target Argonaute2, a component of the microRNA-induced silencing complex. Argonaute2 promotes compensatory β cell proliferation via miR-375 and its target genes, including the growth suppressor Cadm1.