title: The Lin28/let-7 axis regulates glucose metabolism.
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.
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
authors.forename: Ayellet V
authors.initials: AV
authors.lastname: Segrè
authors.forename: Gen
authors.initials: G
authors.lastname: Shinoda
authors.forename: Samar P
authors.initials: SP
authors.lastname: Shah
authors.forename: William S
authors.initials: WS
authors.lastname: Einhorn
authors.forename: Ayumu
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Engreitz
authors.forename: John P
authors.initials: JP
authors.lastname: Hagan
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kharas
authors.forename: Achia
authors.initials: A
authors.lastname: Urbach
authors.forename: James E
authors.initials: JE
authors.lastname: Thornton
authors.forename: Robinson
authors.initials: R
authors.lastname: Triboulet
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse; D005947:Glucose