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PNAS 110 (7): 2557-2562

Copyright © 2013 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

Role for the obesity-related FTO gene in the cellular sensing of amino acids

Pawan Gulatia,b,1, Man Ka Cheunga,b, Robin Antrobusc, Chris D. Churchd, Heather P. Hardinga,b, Yi-Chun Loraine Tunga,b, Debra Rimmingtona,b, Marcella Maa,b, David Rona,b, Paul J. Lehnerc, Frances M. Ashcrofte, Roger D. Coxd, Anthony P. Colla,b, Stephen O’Rahillya,b,1, and Giles S. H. Yeoa,b,1

aUniversity of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, and bNational Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom; cDepartment of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; dMedical Research Council Harwell, Oxfordshire OX11 0RD, United Kingdom; and eDepartment of Physiology, Anatomy, and Genetics, Henry Wellcome Centre for Gene Function, University of Oxford, Oxford OX1 3PT, United Kingdom

Contributed by Stephen O’Rahilly, December 28, 2012 (sent for review December 16, 2012)

Abstract: SNPs in the first intron of FTO (fat mass and obesity associated) are strongly associated with human obesity. While it is not yet formally established that this effect is mediated through the actions of the FTO protein itself, loss of function mutations in FTO or its murine homologue Fto result in severe growth retardation, and mice globally overexpressing FTO are obese. The mechanisms through which FTO influences growth and body composition are unknown. We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing.

Key Words: genetics • translation • tRNA synthetase • demethylase


Freely available online through the PNAS open access option.

Author contributions: P.G., D. Ron, A.P.C., S.O., and G.S.H.Y. designed research; P.G., M.K.C., H.P.H., Y.-C.L.T., D. Rimmington, and M.M. performed research; R.A., C.D.C., H.P.H., Y.-C.L.T., P.J.L., F.M.A., R.D.C., and A.P.C. contributed new reagents/analytic tools; P.G., D. Ron, A.P.C., and G.S.H.Y. analyzed data; and P.G., F.M.A., S.O., and G.S.H.Y. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1222796110/-/DCSupplemental.

1To whom correspondence may be addressed. E-mail: pg367{at}cam.ac.uk, so104{at}medschl.cam.ac.uk, or gshy2{at}cam.ac.uk.


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