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Inactivation of the Fto gene protects from obesity


Several independent, genome-wide association studies have identified a strong correlation between body mass index and polymorphisms in the human FTO gene1,2,3,4. Common variants in the first intron define a risk allele predisposing to obesity, with homozygotes for the risk allele weighing approximately 3 kilograms more than homozygotes for the low risk allele1. Nevertheless, the functional role of FTO in energy homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. The leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia. Taken together, these experiments provide, to our knowledge, the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure.

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Figure 1: Successful generation of Fto-deficient mice.
Figure 2: Phenotypic characteristics of Fto-negative mice.
Figure 3: Body composition of Fto-negative mice.
Figure 4: Parameters of energy uptake and expenditure.


  1. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007)

    Article  ADS  CAS  Google Scholar 

  2. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genet. 39, 724–726 (2007)

    Article  CAS  Google Scholar 

  3. Scott, L. J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007)

    Article  ADS  CAS  Google Scholar 

  4. Scuteri, A. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007)

    Article  Google Scholar 

  5. Peters, T., Ausmeier, K. & Rüther, U. Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation. Mamm. Genome 10, 983–986 (1999)

    Article  CAS  Google Scholar 

  6. Peters, T., Ausmeier, K., Dildrop, R. & Rüther, U. The mouse Fused toes (Ft) mutation is the result of a 1.6-Mb deletion including the entire Iroquois B gene cluster. Mamm. Genome 13, 186–188 (2002)

    Article  CAS  Google Scholar 

  7. van der Hoeven, F. et al. Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development 120, 2601–2607 (1994)

    CAS  PubMed  Google Scholar 

  8. Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472 (2007)

    Article  ADS  CAS  Google Scholar 

  9. Sanchez-Pulido, L. & Andrade-Navarro, M. A. The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily. BMC Biochem. 8, 23 (2007)

    Article  Google Scholar 

  10. Stratigopoulos, G. et al. Regulation of Fto/Ftm gene expression in mice and humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1185–R1196 (2008)

    Article  CAS  Google Scholar 

  11. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994)

    Article  ADS  CAS  Google Scholar 

  12. Caro, J. F., Sinha, M. K., Kolaczynski, J. W., Zhang, P. L. & Considine, R. V. Leptin: the tale of an obesity gene. Diabetes 45, 1455–1462 (1996)

    Article  CAS  Google Scholar 

  13. Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996)

    Article  CAS  Google Scholar 

  14. Waki, H. et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J. Biol. Chem. 278, 40352–40363 (2003)

    Article  CAS  Google Scholar 

  15. Lara-Castro, C., Luo, N., Wallace, P., Klein, R. L. & Garvey, W. T. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 55, 249–259 (2006)

    Article  CAS  Google Scholar 

  16. Pajvani, U. B. et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J. Biol. Chem. 279, 12152–12162 (2004)

    Article  CAS  Google Scholar 

  17. Xu, A. et al. Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J. Biol. Chem. 280, 18073–18080 (2005)

    Article  CAS  Google Scholar 

  18. Coll, A. P., Farooqi, I. S. & O'Rahilly, S. The hormonal control of food intake. Cell 129, 251–262 (2007)

    Article  CAS  Google Scholar 

  19. Fredriksson, R. et al. The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology 149, 2062–2071 (2008)

    Article  CAS  Google Scholar 

  20. Wilson, S. W. & Houart, C. Early steps in the development of the forebrain. Dev. Cell 6, 167–181 (2004)

    Article  CAS  Google Scholar 

  21. Jeon, J. Y. et al. MCH-/- mice are resistant to aging-associated increases in body weight and insulin resistance. Diabetes 55, 428–434 (2006)

    Article  CAS  Google Scholar 

  22. Wardle, J. et al. Obesity associated genetic variation in FTO is associated with diminished satiety. J. Clin. Endocrinol. Metab. 93, 3640–3643 (2008)

    Article  CAS  Google Scholar 

  23. Speakman, J. R., Rance, K. A. & Johnstone, A. M. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring) 16, 1961–1965 (2008)

    Article  CAS  Google Scholar 

  24. Timpson, N. J. et al. The fat mass- and obesity-associated locus and dietary intake in children. Am. J. Clin. Nutr. 88, 971–978 (2008)

    Article  CAS  Google Scholar 

  25. Grunnet, L. G. et al. Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibres and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609. J. Clin. Endocrinol. Metab. 94, 596–602 (2009)

    Article  CAS  Google Scholar 

  26. Lowell, B. B. & Bachman, E. S. β-Adrenergic receptors, diet-induced thermogenesis and obesity. J. Biol. Chem. 278, 29385–29388 (2003)

    Article  CAS  Google Scholar 

  27. Miyoshi, H. et al. Hormonal control of substrate cycling in humans. J. Clin. Invest. 81, 1545–1555 (1988)

    Article  CAS  Google Scholar 

  28. Wolfe, R. R., Herndon, D. N., Jahoor, F., Miyoshi, H. & Wolfe, M. H. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N. Engl. J. Med. 317, 403–408 (1987)

    Article  CAS  Google Scholar 

  29. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J. C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 (1993)

    Article  ADS  CAS  Google Scholar 

  30. Vierkotten, J., Dildrop, R., Peters, T., Wang, B. & Rüther, U. Ftm is a novel basal body protein of cilia involved in Shh signalling. Development 134, 2569–2577 (2007)

    Article  CAS  Google Scholar 

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The authors thank S. Kuschel and B. Hampel for technical assistance, S. Fischer for critical reading of this manuscript, as well as W. Stoffel, B. Jehnke and H. Brönneke for support during assessment of energy expenditure. This work was supported by the Deutsche Forschungsgemeinschaft (to U.R. and J.C.B.) and in part by NGFNplus (to U.R.).

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Correspondence to Jens C. Brüning or Ulrich Rüther.

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Fischer, J., Koch, L., Emmerling, C. et al. Inactivation of the Fto gene protects from obesity. Nature 458, 894–898 (2009).

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