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Cell Metab. 2015 Apr 7;21(4):609-21. doi: 10.1016/j.cmet.2015.03.006.

IGF2BP2/IMP2-Deficient mice resist obesity through enhanced translation of Ucp1 mRNA and Other mRNAs encoding mitochondrial proteins.

Author information

1
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.
2
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.
3
European Molecular Biology Laboratory, Mouse Biology Unit, 00015-Monterotondo, Italy.
4
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.
5
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
6
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
7
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.
8
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.
9
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.
10
European Molecular Biology Laboratory, Mouse Biology Unit, 00015-Monterotondo, Italy; Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
11
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.
12
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.

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.

PMID:
25863250
PMCID:
PMC4663978
DOI:
10.1016/j.cmet.2015.03.006
[Indexed for MEDLINE]
Free PMC Article

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