title: IGF2BP2/IMP2-Deficient mice resist obesity through enhanced translation of Ucp1 mRNA and Other mRNAs encoding mitochondrial proteins.
abstract: Although variants in the IGF2BP2/IMP2 gene confer risk for type 2 diabetes, IMP2, an RNA binding protein, is not known to regulate metabolism. Imp2(-/-) mice gain less lean mass after weaning and have increased lifespan. Imp2(-/-) mice are highly resistant to diet-induced obesity and fatty liver and display superior glucose tolerance and insulin sensitivity, increased energy expenditure, and better defense of core temperature on cold exposure. Imp2(-/-) brown fat and Imp2(-/-) brown adipocytes differentiated in vitro contain more UCP1 polypeptide than Imp2(+/+) despite similar levels of Ucp1 mRNA; the Imp2(-/-)adipocytes also exhibit greater uncoupled oxygen consumption. IMP2 binds the mRNAs encoding Ucp1 and other mitochondrial components, and most exhibit increased translational efficiency in the absence of IMP2. In vitro IMP2 inhibits translation of mRNAs bearing the Ucp1 untranslated segments. Thus IMP2 limits longevity and regulates nutrient and energy metabolism in the mouse by controlling the translation of its client mRNAs.
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Unit, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Ning
authors: N
authors: Dai
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Unit, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors: Liping
authors: L
authors: Zhao
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Diedra
authors: D
authors: Wrighting
authors: European Molecular Biology Laboratory, Mouse Biology Unit, 00015-Monterotondo, Italy.
authors: Dana
authors: D
authors: Krämer
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Unit, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Amit
authors: A
authors: Majithia
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Yanqun
authors: Y
authors: Wang
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Valentin
authors: V
authors: Cracan
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors: Diego
authors: D
authors: Borges-Rivera
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Unit, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Vamsi K
authors: VK
authors: Mootha
authors: Department of Radiology and the Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Matthias
authors: M
authors: Nahrendorf
authors: Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia.
authors: David R
authors: DR
authors: Thorburn
authors: European Molecular Biology Laboratory, Mouse Biology Unit, 00015-Monterotondo, Italy; Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
authors: Liliana
authors: L
authors: Minichiello
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Unit, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: altshuler@molbio.mgh.harvard.edu.
authors: David
authors: D
authors: Altshuler
authors: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Diabetes Unit, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: avruch@molbio.mgh.harvard.edu.
authors: Joseph
authors: J
authors: Avruch
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D001833:Body Temperature Regulation / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009765:Obesity / Q000517:prevention & control*; D016601:RNA-Binding Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D000071256:Uncoupling Protein 1
chemical_list: C559768:IGF2BP2 protein, mouse; D007473:Ion Channels; D024101:Mitochondrial Proteins; D016601:RNA-Binding Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1