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Overexpression of Fto leads to increased food intake and results in obesity

Nature Genetics volume 42, pages 1086–1092 (2010)Cite this article

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Abstract

Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity–associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh, on average, ∼3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice.

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Figure 1: Generation of a mouse model overexpressing Fto.
Figure 2: Fto dose-dependent increases in body weight are observed in male and female mice on standard (SD) and high-fat (HFD) diets.
Figure 3: Body composition varies with Fto copy number.
Figure 4: Effects of Fto on energy intake and plasma leptin.
Figure 5: Effects of Fto on energy expenditure and physical activity.
Figure 6: Glucose homeostasis and Fto overexpression.

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Acknowledgements

We thank the UK Medical Research Council (MRC) (to L.M., L.T., S.W., P.M.N., G.T.B., R.D.C. and studentships to C.C. and F.M.) and the UK Royal Society (research professorship to F.M.A.) for personnel support, and the MRC and Wellcome Trust for financing the research (R.D.C. and F.M.A.). We thank C. Holmes, G. Nicholson and O. Espinosa for help with multiple regression analysis using R.

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Authors and Affiliations

  1. MRC Harwell, Metabolism and Inflammation, Harwell Science and Innovation Campus, Harwell, UK

    Chris Church, Lee Moir, Fiona McMurray, Gareth T Banks, Lydia Teboul, Sara Wells, Patrick M Nolan & Roger D Cox

  2. Department of Physiology, Henry Wellcome Centre for Gene Function, Anatomy and Genetics, University of Oxford, Oxford, UK

    Christophe Girard & Frances M Ashcroft

  3. Center of Molecular Medicine Cologne (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Jens C Brüning

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  1. Chris Church
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Contributions

C.C., R.D.C. and F.M.A. planned the project and wrote the manuscript. C.C., L.M. and F.M. carried out the whole-animal experiments. P.M.N., S.W. and G.T.B. carried out the behavioral and circadian studies. J.C.B. and C.G. provided overexpression vector design, construction and methods. L.T. and C.C. carried out the transgenic work.

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Correspondence to Roger D Cox.

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Church, C., Moir, L., McMurray, F. et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 42, 1086–1092 (2010). https://doi.org/10.1038/ng.713

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