4.8 Article

IGF2BP2/IMP2-Deficient Mice Resist Obesity through Enhanced Translation of Ucp1 mRNA and Other mRNAs Encoding Mitochondrial Proteins

Journal

CELL METABOLISM
Volume 21, Issue 4, Pages 609-621

Publisher

CELL PRESS
DOI: 10.1016/j.cmet.2015.03.006

Keywords

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Funding

  1. NIH [R37DK17776, P30DK057521]
  2. Instituto Carso de la Salud, A.C. via Slim Initiative in Genomic Medicine for the Americas
  3. Lundbeck foundation [177/05]
  4. EMBL
  5. NHMRC

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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.

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