Argonaute2 mediates compensatory expansion of the pancreatic β cell.
Ontology highlight
ABSTRACT:
SUBMITTER: Tattikota SG
PROVIDER: S-EPMC3945818 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pancreatic M-CM-^_-cells adapt to compensate for the increased metabolic demand during insulin resistance. While the microRNA pathway has an essential role in the expansion of M-CM-^_-cell mass, the extent of its contribution is unclear. Here we show that miR-184 is silenced in the pancreatic islets of several insulin-resistant mouse models and in the islets of 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. While over-expression of Ago2 increased M-CM-^_-cell proliferation, conditional deletion decreased M-CM-^_-cell number. Moreover, restored expression of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory M-CM-^_-cell expansion. Loss of Ago2 expression during insulin resistance blocked M-CM-^_-cell growth and relieved the regulation of miR-375-targeted genes including the growth suppressor Cadm1. This study identifies the regulation of Ago2 by miR-184 as an essential component of the compensatory response to promote proliferation during insulin resistance. MIN6 cells were transfected with Doxycyline responsive plasmids including the tetO-184 construct in biological triplicates for every time point. The conditions included untransfected control (CTR, induced), Transfected Control (TC, uninduced) along the time points of miR-184 overexpression in 16, 24, 48, and 72 hours of doxycycline treatment.
2014-02-06 | E-GEOD-46623 | biostudies-arrayexpress
Project description:Pancreatic ß-cells adapt to compensate for the increased metabolic demand during insulin resistance. While the microRNA pathway has an essential role in the expansion of ß-cell mass, the extent of its contribution is unclear. Here we show that miR-184 is silenced in the pancreatic islets of several insulin-resistant mouse models and in the islets of 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. While over-expression of Ago2 increased ß-cell proliferation, conditional deletion decreased ß-cell number. Moreover, restored expression of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory ß-cell expansion. Loss of Ago2 expression during insulin resistance blocked ß-cell growth and relieved the regulation of miR-375-targeted genes including the growth suppressor Cadm1. This study identifies the regulation of Ago2 by miR-184 as an essential component of the compensatory response to promote proliferation during insulin resistance.
2014-02-06 | GSE46623 | GEO
Project description:Argonaute2 (Ago2) is an established component of the microRNA-induced silencing complex. Similar to miR-375 loss-of-function studies, inhibition of Ago2 in the pancreatic β-cell resulted in enhanced insulin release underlining the relationship between these two genes. Moreover, as the most abundant microRNA in pancreatic endocrine cells, miR-375 was also observed to be enriched in Ago2-associated complexes. Both Ago2 and miR-375 regulate the pancreatic β-cell secretome, and by using quantitative mass spectrometry, we identified the enhanced release of a set of proteins or secretion "signatures " in response to a glucose stimulus using the murine β-cell line MIN6. In addition, the loss of Ago2 resulted in the increased expression of miR-375 target genes, including gephyrin and ywhaz. These targets positively contribute to exocytosis indicating they may mediate the functional role of both miR-375 and Ago proteins in the pancreatic β-cell by influencing the secretory pathway. This study specifically addresses the role of Ago2 in the systemic release of proteins from β-cells and highlights the contribution of the microRNA pathway to the function of this cell type.
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Project description:Pregnancy and obesity are frequently associated with diminished insulin sensitivity, which is normally compensated for by an expansion of the functional β cell mass that prevents chronic hyperglycemia and development of diabetes mellitus. The molecular basis underlying compensatory β cell mass expansion is largely unknown. We found in rodents that β cell mass expansion during pregnancy and obesity is associated with changes in the expression of several islet microRNAs, including miR-338-3p. In isolated pancreatic islets, we recapitulated the decreased miR-338-3p level observed in gestation and obesity by activating the G protein-coupled estrogen receptor GPR30 and the glucagon-like peptide 1 (GLP1) receptor. Blockade of miR-338-3p in β cells using specific anti-miR molecules mimicked gene expression changes occurring during β cell mass expansion and resulted in increased proliferation and improved survival both in vitro and in vivo. These findings point to a major role for miR-338-3p in compensatory β cell mass expansion occurring under different insulin resistance states.
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