Nature Medicine
7, 1128 - 1132 (2001)
doi:10.1038/nm1001-1128
Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1Kyoko Tsukiyama-Kohara1, 2, 6, 7, Francis Poulin1, 7, Michinori Kohara2, Christine T. DeMaria1, Alan Cheng1, Zhidan Wu3, Anne-Claude Gingras1, Asao Katsume2, 4, Mounib Elchebly1, Bruce M. Spiegelman3, Mary-Ellen Harper5, Michel L. Tremblay1
& Nahum Sonenberg11
Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada
2
Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
3
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
4
Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Shizuoka, Japan
5
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
6
Institute of Medical Science, The University of Tokyo, Tokyo, Japan
7
K.T.-K. and F.P. contributed equally to this study.
Correspondence should be addressed to Nahum Sonenberg nsonen@med.mcgill.caAll nuclear-encoded mRNAs contain a 5' cap structure (m7GpppN, where N is any nucleotide), which is recognized by the eukaryotic translation initiation factor 4E (eIF4E) subunit of the eIF4F complex. The eIF4E-binding proteins constitute a family of three polypeptides that reversibly repress cap-dependent translation by binding to eIF4E, thus preventing the formation of the eIF4F complex. We investigated the biological function of 4E-BP1 by disrupting its gene (Eif4ebp1) in the mouse. Eif4ebp1
-/- mice manifest markedly smaller white fat pads than wild-type animals, and knockout males display an increase in metabolic rate. The males' white adipose tissue contains cells that exhibit the distinctive multilocular appearance of brown adipocytes, and expresses the uncoupling protein 1 (UCP1), a specific marker of brown fat. Consistent with these observations, translation of the peroxisome proliferator-activated receptor- co-activator 1 (PGC1), a transcriptional co-activator implicated in mitochondrial biogenesis and adaptive thermogenesis, is increased in white adipose tissue of Eif4ebp1
-/- mice. These findings demonstrate that 4E-BP1 is a novel regulator of adipogenesis and metabolism in mammals.
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