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The Lin28/let-7 axis regulates glucose metabolism.

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.

Pubmed ID: 21962509

Authors

  • Zhu H
  • Shyh-Chang N
  • Segrè AV
  • Shinoda G
  • Shah SP
  • Einhorn WS
  • Takeuchi A
  • Engreitz JM
  • Hagan JP
  • Kharas MG
  • Urbach A
  • Thornton JE
  • Triboulet R
  • Gregory RI
  • DIAGRAM Consortium
  • MAGIC Investigators
  • Altshuler D
  • Daley GQ

Journal

Cell

Publication Data

September 30, 2011

Associated Grants

  • Agency: Wellcome Trust, Id: 090532
  • Agency: Medical Research Council, Id: G0100222
  • Agency: Medical Research Council, Id: G0902037
  • Agency: Medical Research Council, Id: G19/35
  • Agency: Medical Research Council, Id: G8802774
  • Agency: NCI NIH HHS, Id: K08 CA157727
  • Agency: Medical Research Council, Id: MC_PC_U127561128
  • Agency: Medical Research Council, Id: MC_U127561128
  • Agency: Medical Research Council, Id: MC_UP_A100_1003
  • Agency: Medical Research Council, Id: MC_UP_A620_1015
  • Agency: NIDDK NIH HHS, Id: R01 DK070055
  • Agency: British Heart Foundation, Id: RG/07/008/23674
  • Agency: NCI NIH HHS, Id: T32 CA009172
  • Agency: Medical Research Council, Id: U1475000002
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Diabetes Mellitus, Type 2
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • Glucose
  • Humans
  • Insulin Resistance
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • MicroRNAs
  • Obesity
  • RNA-Binding Proteins