Author/Authors :
Hao Zhu، نويسنده , , Ng Shyh-Chang، نويسنده , , Ayellet V. Segrè، نويسنده , , Gen Shinoda، نويسنده , , Samar P. Shah، نويسنده , , William S. Einhorn، نويسنده , , Ayumu Takeuchi، نويسنده , , Jesse M. Engreitz، نويسنده , , John P. Hagan، نويسنده , , Michael G. Kharas، نويسنده , , Achia Urbach، نويسنده , , James E. Thornton، نويسنده , , Robinson Triboulet، نويسنده , , Richard I. Gregory، نويسنده , , DIAGRAM Consortium، نويسنده , , for the MAGIC Investigators، نويسنده , , David Altshuler، نويسنده , , George Q. Daley، نويسنده ,
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.