期刊
CELL
卷 147, 期 1, 页码 81-94出版社
CELL PRESS
DOI: 10.1016/j.cell.2011.08.033
关键词
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资金
- US NIH
- Graduate Training in Cancer Research Grant
- American Cancer Society
- Agency for Science, Technology and Research, Singapore
- NIH NIDDK
- American Diabetes Association
- National Human Genome Research Institute (NHGRI)
- US National Institute of General Medical Sciences (NIGMS)
- Burroughs Wellcome Fund
- Leukemia and Lymphoma Society
- MRC [G0902037, MC_U127561128, MC_PC_U127561128, MC_UP_A620_1015, MC_UP_A100_1003] Funding Source: UKRI
- British Heart Foundation [RG/07/008/23674] Funding Source: researchfish
- Medical Research Council [G8802774, U1475000002, MC_UP_A100_1003, G19/35, MC_UP_A620_1015, MC_PC_U127561128, G0100222, MC_U127561128, G0902037] Funding Source: researchfish
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, them TOR 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.
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