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 language | English (US) |
|---|---|
| Pages (from-to) | 81-94 |
| Number of pages | 14 |
| Journal | Cell |
| Volume | 147 |
| Issue number | 1 |
| DOIs | |
| State | Published - Sep 30 2011 |
| Externally published | Yes |
Funding
We thank John Powers, Harith Rajagopalan, Jason Locasale, Abdel Saci, Akash Patnaik, Charles Kaufman, Christian Mosimann and Lewis Cantley for invaluable discussions and advice, Roderick Bronson and the Harvard Medical School Rodent Histopathology Core for mouse tissue pathology, and the Harvard Neurobehavior Laboratory for CLAMS experiments. This work was supported by grants from the US NIH to G.Q.D., a Graduate Training in Cancer Research Grant and a American Cancer Society Postdoctoral Fellowship to H.Z., the NSS Scholarship from the Agency for Science, Technology and Research, Singapore for N.S.C, an NIH NIDDK Diseases Career Development Award to M.G.K, and an American Diabetes Association Postdoctoral Fellowship for A.V.S. J.M.E. was supported by the National Human Genome Research Institute (NHGRI). R.I.G. was supported by US National Institute of General Medical Sciences (NIGMS) and is a Pew Research Scholar. D.A. is a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. G.Q.D. is a recipient of Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. H.Z. and N.S.C designed and performed the experiments, and wrote the manuscript. A.V.S. and D.A. performed bioinformatic analysis on let-7 targets in GWAS. G.S. and S.P.S. performed expression analysis, metabolic assays and mouse husbandry. G.S., W.S.E. and A.T. generated the mouse strains. J.E.T, R.T. and R.I.G. assisted with the luciferase assays. J.P.H., R.I.G., G.S., and A.T generated the conditional knockout mice. M.G.K. helped to design the experiments. G.Q.D. designed and supervised experiments, and wrote the manuscript. The authors declare no competing financial interests.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
