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Zhu, H.* ; Shyh-Chang, N.* ; Segrè, A.V.* ; Shinoda, G.* ; Shah, S.P.* ; Einhorn, W.S.* ; Takeuchi, A.* ; Engreitz, J.M.* ; Hagan, J.P.* ; Kharas, M.G.* ; Urbach, A.* ; Thornton, J.E.* ; Triboulet, R.* ; Gregory, R.I* ; DIAGRAM Consortium (Huth, C. ; Grallert, H. ; Gieger, C. ; Klopp, N. ; Meitinger, T. ; Petersen, A.-K. ; Thorand, B. ; Wichmann, H.-E. ; Illig, T.) ; MAGIC Investigators (Grallert, H. ; Gieger, C. ; Meisinger, C. ; Thorand, B. ; Wichmann, H.-E. ; Illig, T.) ; Altshuler, D.* ; Daley, G.Q.*

The Lin28/let-7 axis regulates glucose metabolism.

Cell 147, 81-94 (2011)
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The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Let-7 microrna family; Human hepatocellular-carcinoma; Caenorhabditis-elegans; Promotes transformation; Insulin-resistance; Tansgenic mice; Messenger- RNA; Stem-cells; LIN-28; LIN28
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 147, Issue: 1, Pages: 81-94 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed