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Elsevier, Cell, 1(147), p. 81-94, 2011

DOI: 10.1016/j.cell.2011.08.033

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The Lin28/let-7 axis regulates glucose metabolism

Journal article published in 2011 by Hao Zhu ORCID, Ng Shyh-Chang, Ayellet V. Segrè, Gen Shinoda, Samar P. Shah, William S. Einhorn, Ayumu Takeuchi, Jesse Michael Engreitz, John P. Hagan, Michael G. Kharas, Achia Urbach, James E. Thornton, Robinson Triboulet, Richard I. Gregory, David Altshuler and other authors.
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This paper is available in a repository.

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Abstract

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by blocking let-7 biogenesis. In studies of the Lin28/let-7 pathway, we discovered unexpected roles in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promoted an insulin-sensitized state that resisted high fat diet-induced diabetes, whereas muscle-specific loss of Lin28a and overexpression of let-7 resulted in insulin resistance and impaired glucose tolerance. These phenomena occurred in part through let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. The mTOR inhibitor rapamycin abrogated the enhanced glucose uptake and insulin-sensitivity conferred by Lin28a in vitro and in vivo. In addition, we found that let-7 targets were enriched for genes that contain SNPs associated with type 2 diabetes and fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.