Abstract
Replying to: J. R. Speakman Nature 464, 10.1038/nature08807 (2010)
The human studies on FTO reported an association of an intronic single nucleotide polymorphism (SNP) with obesity. Our report of mice with the targeted inactivation of the Fto gene demonstrated a direct role of Fto in energy homeostasis1. We have shown that the absence of Fto protein results in leanness and that Fto deficiency affects energy homeostasis. Speakman2 exemplifies that the experiments performed in mice1 conflict with results in humans carrying the FTO risk allele presenting hyperphagia and increased caloric intake3,4,5,6,7,8,9.
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The majority of studies examining the effects of FTO risk SNPs and determinants of adiposity in humans have reported association with food intake and/or appetite, and none has reported a significant effect on energy expenditure. However, the effects are modest in size and the precise measurement of the components of energy balance in human is fraught with difficulty, so it would therefore be premature to state conclusively that FTO affects human adiposity only through an effect on food intake.
With respect to the analysis of energy expenditure in our mouse model, correction of energy expenditure, that is, O2 consumption to lean body mass, represents at this point a standard procedure in mouse phenotyping. This kind of data analysis was specifically requested by the reviewers of our manuscript. Another group has since reported the generation and analysis of a mouse model carrying a point mutation in the murine Fto gene as a consequence of N-ethyl-N-nitrosourea mutagenesis10. The phenotype of this mouse line closely resembles the knockout phenotype1, although the alterations in overall body size are much more moderate.
However, this model also presents reduced fat mass and resistance to high-fat-induced obesity. Notably, in line with our report, even in the absence of major weight differences and with unaltered lean mass, mice carrying the Fto point mutation show increased energy expenditure as reported for the knockout model10.
Taken together, our report on Fto-deficient mice provides a direct study on the role of the Fto protein in the absence of dysregulated Ftm (also known as Rpgrip1l) expression, the key findings of which have already been reproduced in an independent mouse model with altered Fto function. The observed reduction in fat mass does represent an important step towards the further understanding of FTO biology and we are confident that this and other mouse models will provide important additional insights into the function of FTO in the near future.
References
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Fischer, J., Koch, L., Emmerling, C. et al. Fischer et al. reply. Nature 464, E2 (2010). https://doi.org/10.1038/nature08808
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DOI: https://doi.org/10.1038/nature08808
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