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

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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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.

Corresponding author

Correspondence to Roger D Cox.

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The authors declare no competing financial interests.

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Supplementary Figures 1–9, Supplementary Tables 1–3 and Supplementary Note (PDF 1779 kb)

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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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