Inactivation of the Fto gene protects from obesity

Abstract

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.

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Acknowledgements

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). https://doi.org/10.1038/nature07848

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