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The Lin28/let-7 axis regulates glucose metabolism.

Cell | Sep 30, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21962509

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 RIS Download

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

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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: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

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