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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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)
Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genet. 39, 724–726 (2007)
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)
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)
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)
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)
van der Hoeven, F. et al. Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development 120, 2601–2607 (1994)
Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472 (2007)
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)
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)
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994)
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)
Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996)
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)
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)
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)
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)
Coll, A. P., Farooqi, I. S. & O'Rahilly, S. The hormonal control of food intake. Cell 129, 251–262 (2007)
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)
Wilson, S. W. & Houart, C. Early steps in the development of the forebrain. Dev. Cell 6, 167–181 (2004)
Jeon, J. Y. et al. MCH-/- mice are resistant to aging-associated increases in body weight and insulin resistance. Diabetes 55, 428–434 (2006)
Wardle, J. et al. Obesity associated genetic variation in FTO is associated with diminished satiety. J. Clin. Endocrinol. Metab. 93, 3640–3643 (2008)
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)
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)
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)
Lowell, B. B. & Bachman, E. S. β-Adrenergic receptors, diet-induced thermogenesis and obesity. J. Biol. Chem. 278, 29385–29388 (2003)
Miyoshi, H. et al. Hormonal control of substrate cycling in humans. J. Clin. Invest. 81, 1545–1555 (1988)
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)
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)
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)
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.).
Author information
Authors and Affiliations
Corresponding authors
Supplementary information
Supplementary Figures
This file contains Supplementary Figures S1-S5 with Legends (PDF 548 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature07848
This article is cited by
-
Epitranscriptomics in metabolic disease
Nature Metabolism (2023)
-
FTO-mediated m6A demethylation regulates GnRH expression in the hypothalamus via the PLCβ3/Ca2+/CAMK signalling pathway
Communications Biology (2023)
-
The rs1421085 variant within FTO promotes brown fat thermogenesis
Nature Metabolism (2023)
-
Adipocyte YTH N(6)-methyladenosine RNA-binding protein 1 protects against obesity by promoting white adipose tissue beiging in male mice
Nature Communications (2023)
-
Genomic correlation, shared loci, and causal relationship between obesity and polycystic ovary syndrome: a large-scale genome-wide cross-trait analysis
BMC Medicine (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.