Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1

All nuclear-encoded mRNAs contain a 5' cap structure (m(7)GpppN, where N is any nucleotide), which is recognized by the eukaryotic translation initiat ion factor 4E (eIF4E) subunit of the eIF4F complex. The elF4E-binding prote ins constitute a family of three polypeptides that reversibly repress cap-d ependent translation by binding to eIF4E, thus preventing the formation of the eIF4F complex. We investigated the biological function of 4E-BP1 by dis rupting its gene (Eif4ebp1) in the mouse. Eif4ebp1(-/-) mice manifest marke dly smaller white fat pads than wild-type animals, and knockout males displ ay an increase in metabolic rate. The males' white adipose tissue contains cells that exhibit the distinctive multilocular appearance of brown adipocy tes, and expresses the uncoupling protein 1 (UCP1), a specific marker of br own fat. Consistent with these observations, translation of the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC1), a transcriptio nal co-activator implicated in mitochondrial biogenesis and adaptive thermo genesis, is increased in white adipose tissue of Eif4ebp1(-/-) mice. These findings demonstrate that 4E-BP1 is a novel regulator of adipogenesis and m etabolism in mammals.