The Lin28/let-7 axis regulates glucose metabolism

Hao Zhu, Shyh Chang Ng, Ayellet V. Segr, Gen Shinoda, Samar P. Shah, William S. Einhorn, Ayumu Takeuchi, Jesse M. Engreitz, John P. Hagan, Michael G. Kharas, Achia Urbach, James E. Thornton, Robinson Triboulet, Richard I. Gregory, David Altshuler, George Q. Daley

Research output: Contribution to journalArticle

502 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)81-94
Number of pages14
JournalCell
Volume147
Issue number1
DOIs
StatePublished - Sep 30 2011

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Metabolism
Insulin
Glucose
Insulin Resistance
Medical problems
RNA-Binding Proteins
Glucose Intolerance
Genes
Genome-Wide Association Study
High Fat Diet
Human Genome
Sirolimus
MicroRNAs
Phosphatidylinositol 3-Kinases
Oncogenes
Type 2 Diabetes Mellitus
Single Nucleotide Polymorphism
Fasting
Neoplasms
Nutrition

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhu, H., Ng, S. C., Segr, A. V., Shinoda, G., Shah, S. P., Einhorn, W. S., ... Daley, G. Q. (2011). The Lin28/let-7 axis regulates glucose metabolism. Cell, 147(1), 81-94. https://doi.org/10.1016/j.cell.2011.08.033

The Lin28/let-7 axis regulates glucose metabolism. / Zhu, Hao; Ng, Shyh Chang; Segr, 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.; Altshuler, David; Daley, George Q.

In: Cell, Vol. 147, No. 1, 30.09.2011, p. 81-94.

Research output: Contribution to journalArticle

Zhu, H, Ng, SC, Segr, AV, Shinoda, G, Shah, SP, Einhorn, WS, Takeuchi, A, Engreitz, JM, Hagan, JP, Kharas, MG, Urbach, A, Thornton, JE, Triboulet, R, Gregory, RI, Altshuler, D & Daley, GQ 2011, 'The Lin28/let-7 axis regulates glucose metabolism', Cell, vol. 147, no. 1, pp. 81-94. https://doi.org/10.1016/j.cell.2011.08.033
Zhu H, Ng SC, Segr AV, Shinoda G, Shah SP, Einhorn WS et al. The Lin28/let-7 axis regulates glucose metabolism. Cell. 2011 Sep 30;147(1):81-94. https://doi.org/10.1016/j.cell.2011.08.033
Zhu, Hao ; Ng, Shyh Chang ; Segr, 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. ; Altshuler, David ; Daley, George Q. / The Lin28/let-7 axis regulates glucose metabolism. In: Cell. 2011 ; Vol. 147, No. 1. pp. 81-94.
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