The Lin28/let-7 axis regulates glucose metabolism

By Hao Zhu, Ng Shyh‐Chang, A. Segrè, Gen Shinoda, Samar P. Shah, William S. Einhorn, A. Takeuchi, J. Engreitz, J. Hagan, M. Kharas and 6 more. Cell, 2011

897 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9f45b17347d26b91fcaadb5b357f023cc8f7803c

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Citations in the corpus

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination (2016, background): “Although the role of PI3K/AKT/mTOR in this process has not been fully uncovered, several reports have demonstrated that PI3K/ AKT signalling promotes iPSC generation through inhibition of GSK3β and FOXO1, while concurrently enhancing the glycolytic metabolism (Silva et al., 2008; Yu et al., 2014; Zh”
The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs (2013, background): “Because let-7 has been implicated in regulating glucose metabolism in muscle (Frost and Olson, 2011; Zhu et al., 2011), we speculate that H19 may modulate let-7 action in this organ, thereby contributing to glucose metabolism regulation.”
An overview of microRNAs (2015, background): “let-7 in the pancreas leads to reduced glucose tolerance, while overexpression of the let-7 inhibitory protein Lin28 improves glucose uptake[190, 191].”
Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. (2012, neutral): “Combined with our findings on LIN28, which has been shown to promote glucose uptake and glycolysis (Zhu et al., 2010, 2011), GLDC might be cooperating with LIN28 as well as PSAT1, PSPH, and SHMT1/2 to divert the glycolytic flux to glycine and produce CH2-THF.”