High-speed automatic characterization of rare events in flow cytometric data

10.1371/journal.pone.0228651PLoS ONE152e022865

The <em>Lin28/let-7</em> 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

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.National Institutes of Health (U.S.)Singapore. Agency for Science, Technology and Research (NSS Scholarship)American Cancer Society (Postdoctoral Fellowship)National Institutes of Health (U.S.) (NIH NIDDK Diseases Career Development Award)American Diabetes Association (Postdoctoral Fellowship)National Human Genome Research Institute (U.S.)National Institute of General Medical Sciences (U.S.)Pew Charitable Trusts (Pew Research Scholar)Doris Duke Charitable Foundation (Distinguished Clinical Scholar)Burroughs Wellcome Fund (Clinical Scientist Award in Translational Research)Leukemia & Lymphoma Society of America (Clinical Scientist Award in Translational Research)Howard Hughes Medical Institute (Investigator)Boston Children's Hospital (Manton Center for Orphan Disease Research, Investigator)American Cancer Society (Graduate Training in Cancer Research Grant