Current Obesity Reports

, Volume 4, Issue 1, pp 73–91 | Cite as

The ‘Fat Mass and Obesity Related’ (FTO) gene: Mechanisms of Impact on Obesity and Energy Balance

  • John R. SpeakmanEmail author
Psychological Issues (M Hetherington and V Drapeau, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Psychological Issues


A cluster of single nucleotide polymorphisms (SNPs) in the first intron of the fat mass and obesity related (FTO) gene were the first common variants discovered to be associated with body mass index and body fatness. This review summarises what has been later discovered about the biology of FTO drawing together information from both human and animal studies. Subsequent work showed that the ‘at risk’ alleles of these SNPs are associated with greater food intake and increased hunger/lowered satiety, but are not associated with altered resting energy expenditure or low physical activity in humans. FTO is an FE (II) and 2-oxoglutarate dependent DNA/RNA methylase. Contrasting the impact of the SNPs on energy balance in humans, knocking out or reducing activity of the Fto gene in the mouse resulted in lowered adiposity, elevated energy expenditure with no impact on food intake (but the impact on expenditure is disputed). In contrast, overexpression of the gene in mice led to elevated food intake and adiposity, with no impact on expenditure. In rodents, the Fto gene is widely expressed in the brain including hypothalamic nuclei linked to food intake regulation. Since its activity is 2-oxoglutarate dependent it could potentially act as a sensor of citrate acid cycle flux, but this function has been dismissed, and instead it has been suggested to be much more likely to act as an amino acid sensor, linking circulating AAs to the mammalian target of rapamycin complex 1. This may be fundamental to its role in development but the link to obesity is less clear. It has been recently suggested that although the obesity related SNPs reside in the first intron of FTO, they may not only impact FTO but mediate their obesity effects via nearby genes (notably RPGRIP1L and IRX3).


FTO GWAS BMI Body composition Adiposity Fatness Obesity Food intake Energy expenditure Physical activity 2-oxoglutarate Demethylation DNA RNA Leptin Ghrelin Hypothalamus Amino acid sensor mTOR Protein intake Macronutrient intake IRX3 RPGRIP1L FTM 


Compliance with Ethics Guidelines

Conflict of Interest

John R. Speakman declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
  2. 2.Institute of Biological and Environmental SciencesUniversity of AberdeenAberdeenUK

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