The Lin28/let-7 axis regulates glucose metabolism

Zhu, Hao, Shyh-Chang, Ng, Segrè, Ayellet V., Shinoda, Gen, Shah, Samar P., Einhorn, William S., Takeuchi, Ayumu, Engreitz, Jesse M., Hagan, John P., Kharas, Michael G., Urbach, Achia, Thornton, James E., Triboulet, Robinson, Gregory, Richard I., DIAGRAM Consortium, MAGIC Investigators, Altshuler, David, Daley, George Q. and Coin, Lachlan J. M. (2011) The Lin28/let-7 axis regulates glucose metabolism. Cell, 147 1: 81-94. doi:10.1016/j.cell.2011.08.033

Author Zhu, Hao
Shyh-Chang, Ng
Segrè, Ayellet V.
Shinoda, Gen
Shah, Samar P.
Einhorn, William S.
Takeuchi, Ayumu
Engreitz, Jesse M.
Hagan, John P.
Kharas, Michael G.
Urbach, Achia
Thornton, James E.
Triboulet, Robinson
Gregory, Richard I.
DIAGRAM Consortium
MAGIC Investigators
Altshuler, David
Daley, George Q.
Coin, Lachlan J. M.
Title The Lin28/let-7 axis regulates glucose metabolism
Formatted title
The Lin28/let-7 axis regulates glucose metabolism
Journal name Cell   Check publisher's open access policy
ISSN 0092-8674
Publication date 2011-09-30
Sub-type Article (original research)
DOI 10.1016/j.cell.2011.08.033
Open Access Status DOI
Volume 147
Issue 1
Start page 81
End page 94
Total pages 14
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Subject 1300 Biochemistry, Genetics and Molecular Biology
Formatted abstract
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.

Lin28a/b promote glucose tolerance and insulin-sensitivity in mice ► Overexpression of let-7 microRNA impairs glucose tolerance in mice ► Lin28a/b promote and the let-7's repress components of insulin-PI3K-mTOR signaling ► Let-7 targets are enriched for type II diabetes-associated SNPs in human GWAS
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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