TY - JOUR
T1 - Argonaute2 mediates compensatory expansion of the pancreatic β cell
AU - Tattikota, Sudhir G.
AU - Rathjen, Thomas
AU - McAnulty, Sarah J.
AU - Wessels, Hans Hermann
AU - Akerman, Ildem
AU - Van De Bunt, Martijn
AU - Hausser, Jean
AU - Esguerra, Jonathan L.S.
AU - Musahl, Anne
AU - Pandey, Amit K.
AU - You, Xintian
AU - Chen, Wei
AU - Herrera, Pedro L.
AU - Johnson, Paul R.
AU - O'Carroll, Donal
AU - Eliasson, Lena
AU - Zavolan, Mihaela
AU - Gloyn, Anna L.
AU - Ferrer, Jorge
AU - Shalom-Feuerstein, Ruby
AU - Aberdam, Daniel
AU - Poy, Matthew N.
N1 - Funding Information:
This work was funded by the Helmholtz Gemeinschaft, an ERC Starting Grant (IsletVasc 260744), the Fritz Thyssen Stiftung, the Deutsches Zentrum fuer Herz-Kreislauf Forschung, E.V. (DZHK), ANR11-03 erare2-SkinDev (to D.A.), Swedish Diabetes Association, Swedish Research Council, and the Wellcome Trust (095101/Z/10/Z [to A.L.G.] and 101033/Z/13/Z [to J.F.]). The authors thank L.v.d. Weyden for providing the Cadm1 knockout mouse and T. Horvath, M. Landthaler, T. Willnow, M. Gotthardt, F. Spagnoli, R. Schweiker, K.L. Brayman, H.P. Rahn, M. Richter, A. Sporbert, and the MDC Microscopy Core Facility for assistance in conducting this work.
PY - 2014/1/7
Y1 - 2014/1/7
N2 - 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.
AB - 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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U2 - 10.1016/j.cmet.2013.11.015
DO - 10.1016/j.cmet.2013.11.015
M3 - Article
C2 - 24361012
AN - SCOPUS:84891867862
VL - 19
SP - 122
EP - 134
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 1
ER -